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References to Work on Conus Toxins (A-Z, annotated)

(See also selected references of B.M. Olivera and colleagues on Conotoxins, some books on cone shells, a Bibliography of Conus references (1) ; (2); "What's New in 1999", "2000", "2001", or search the database using the NCBI Entrez Browser).
See also - Marco Bettocchi's Conus Bibliography. Link here for a list of Journals on the web .
Link here for a List of earlier Books / Journal Articles on Venomous Cones


Latest addition :

Miljanich, G.P. (2004) Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem. 2004 Dec;11(23):3029-3040.
Elan Pharmaceuticals, Inc., 7475 Lusk Boulevard, San Diego, CA 92121, USA. george.miljanich@elan.com

Abstract: Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.

Livett, B.G., Gayler, K.R., Khalil, Z. (2004) Drugs from the sea: conopeptides as potential therapeutics. Curr Med Chem. 11: 1715-1723.
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.
Abstract:Marine cone snails from the genus Conus are estimated to consist of up to 700 species. These predatory molluscs have devised an efficient venom apparatus that allows them to successfully capture polychaete worms, other molluscs or in some cases fish as their primary food sources. The toxic venom used by the cone shells contains up to 50 different peptides that selectively inhibit the function of ion channels involved in the transmission of nerve signals in animals. Each of the 700 Conus species contains a unique set of peptides in their venom. Across the genus Conus, the conotoxins represent an extensive array of ion channel blockers each showing a high degree of selectivity for particular types of channels. We have undertaken a study of the conotoxins from Australian species of Conus that have the capacity to inhibit specifically the nicotinic acetylcholine receptors in higher animals. These conotoxins have been identified by mass spectroscopy and their peptide sequences in some cases deduced by the application of modern molecular biology to the RNA extracted from venom ducts. The molecular biological approach has proven more powerful than earlier protein/peptide based technique tor the detection of novel conotoxins [1,2]. Novel conotoxins detected in this way have been further screened for their abilities to modify the responses of tissues to pain stimuli as a first step in describing their potential as lead compounds for novel drugs. This review describes the progress made by several research groups to characterise the properties of conopeptides and to use them as drug leads for the development of novel therapeutics for the treatment of a range of neurological conditions.

Alonso D., Khalil Z., Satkunanathan N. and Livett B.G. (2003) Drugs From the Sea: Conotoxins as Drug Leads for Neuropathic Pain and Other Neurological Conditions. Mini Reviews in Medicinal Chemistry 3: 785-787
Abstract:The oceans are a source of a large group of structurally unique natural products that are mainly found in invertebrates such as sponges, tunicates, bryozoans, and molluscs. It is interesting to note that the majority of marine compounds currently in clinical trials or under preclinical evaluation are produced by these species rather than as secondary metabolites by marine algae [1]. Through the combined efforts of marine natural products chemists and pharmacologists a number of promising compounds have been identified that are either already at advanced stages of clinical trials such as the new anti-cancer drug marine alkaloid ecteinascidin 743 [2], or have been selected as promising candidates for extended preclinical evaluation [3]. This is the case for conotoxins, (Table 1) where a number of conopeptides are currently being developed as analgesics for the treatment of neuropathic pain. PMID: 14529519 [PubMed - in process]

Aneiros, A. and Garateix, A.(2004) Bioactive peptides from marine sources: pharmacological properties and isolation procedures. J Chromatogr B Analyt Technol Biomed Life Sci. 803: 41-53.
Centre of Marine Bioactive Substances (CEBIMAR), Ministry of Science Technology and Environment, PO Box 10600, Loma y 37, Alturas del Vedado, Ciudad, Habana, Cuba. cebimar@infomed.sld.cu Marine organisms represent a valuable source of new compounds. The biodiversity of the marine environment and the associated chemical diversity constitute a practically unlimited resource of new active substances in the field of the development of bioactive products. In this paper, the molecular diversity of different marine peptides is described as well as information about their biological properties and mechanisms of action is provided. Moreover, a short review about isolation procedures of selected bioactive marine peptides is offered. Novel peptides from sponges, ascidians, mollusks, sea anemones and seaweeds are presented in association with their pharmacological properties and obtainment methods.

ARGONAUTA Publishes Cone Articles
Cone collectors are having a field day! Now, along with the new Manual of the Conidae, Vol. 1, everything's coming up cones! The Argonauta, quarterly journal of the International Association of Malacology (A.M.I.), has three cone articles in recent issues. E. Rolán and G. Raybaudi Massila have "Spawning and Development of Mediterranean Conus: aquarium observations" in the Vol. IX (1-6) June 1995 issue, and the whole of Vol. VIII is a Conus number. December 1994 (7-12) contains D. Röckel's Conus: tuberculosus Tomlin, 1937, a disregarded Conus species" and the 61-page extensive "New Investigation on the radular teeth of Conus -- Part II" by Rolán and Massila, heavily illustrated with full-page color plates of Conus. (Part I was published in Vol VIII, No. 1-6, along with W. Korn's "An attempt in SEM Studies of Conus Egg Capsules.") For more information about these articles or for a subscription ($50.00 per year to U.S.), write Roberto Ubaldi, President, A.M.I., Vicolo del Fosso del Fontanile, 20, 1125 Acilia, Roma, Italy.


ALPHABETICAL LISTING

Abbott, (1967). Venom apparatus and geographical distribution of Conus gloriamaris. 8pp., 4figs.

Adams, M.E. and B.M. Olivera (1994) Neurotoxins: Overview of an emerging research technology. TINS 17: 151-155.
Dept of Entomology, University of California, Riverside 92521.
Abstract: Neurotoxins have highly specific actions on molecular targets, and thus offer an effective means of characterizing the growing number of identified ion channels and receptors in the nervous system. This article and the Neurotoxins Supplement accompanying this issue of TINS provide a convenient reference source to facilitate the use of toxins as selective, diagnostic ligands in research. However, while many toxins exert potent actions on target receptors, it must be emphasized that their effects can be complex, and certain general pitfalls often become apparent. Some examples will be given illustrating these complexities and their impact on experimental interpretation. In addition, the potential for the purposeful creation of new 'designer' toxins using molecular cloning will also be addressed.

David J. Adams 1 *, Paul F. Alewood 2, David J. Craik 2, Roger D. Drinkwater 3, Richard J. Lewis 1 2 (1999) Conotoxins and their potential pharmaceutical applications Dev. Res. 46:219-234, 1999. .
1Department of Physiology and Pharmacology, University of Queensland, Brisbane, QLD, Australia 2Centre for Drug Design and Development, University of Queensland, Brisbane, QLD, Australia 3CSIRO, Gehrmann Laboratories, University of Queensland, Brisbane, QLD, Australia

Abstract: The neurotoxins isolated from cone shell venoms are a diverse group of small, disulfide-rich peptides. Most of the active peptides isolated to date have been shown to specifically target various components of neural transmission, and have generally demonstrated high specificities for ion channel and receptor types and subtypes. The specificity of conotoxins is one of the attributes that make them valuable diagnostic tools in the characterisation of neural pathways, as therapeutic agents in medicine, and potentially as biodegradable toxic agents in agroveterinary applications. The number of novel, active peptides within the numerous Conus species is considered to be enormous. Currently, however, relatively few peptides have been characterised. In this article, we review current research on conotoxins with a focus on drug potential being developed at the University of Queensland, Australia. Drug © 1999 Wiley-Liss, Inc.

Adams, M.E., Myers, R.A., Imperial, J.S. and Olivera, B.M. (1993) Toxityping rat brain calcium channels with omega-toxins from spider and cone snail venoms. Biochemistry, 32: 12566-12571. .
Abstract: The synthesis of (I) omega-agatoxins and (I) omega-conotoxins and their use as radioligands to distinguish putatitive binding sites on calcium channels are described. Omega-toxins such as omega-Aga-IIIA and omega-Aga-IVA prepared from spider venom and omega-CTX-MVIIC prepared from snail venom, are high affinity receptor binders in rat brain. These ligands show high specificity for calcium channels.

Akiyama T, Yamazaki T, Mori H, Sunagawa K (2004) Effects of Ca2+ channel antagonists on acetylcholine and catecholamine releases in the in vivo rat adrenal medulla. . Am J Physiol Regul Integr Comp Physiol. Mar 18 [Epub ahead of print].
Drs. Akiyama , Yamazaki, Mori, and Sunagawa from the Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan, have used conotoxin GVIA and MVIIC to provide evidence for the differential involvement of calcium channels in the release of adrenaline and noradrenaline from rat chromaffin cells in-vivo.


Abstract: To elucidate the types of voltage-dependent Ca(2+) channels controlling acetylcholine and catecholamine releases in the in vivo adrenal medulla, we implanted microdialysis probes in the left adrenal medulla of anesthetized rats and investigated the effects of Ca(2+) channel antagonists on acetylcholine, norepinephrine, and epinephrine releases induced by nerve stimulation. The dialysis probes were perfused with Ringer's solution containing a cholinesterase inhibitor, neostigmine. The left splanchnic nerves were electrically stimulated at 2 and 4 Hz before and after intravenous administration of Ca(2+) channel antagonists. omega-Conotoxin GVIA (an N-type Ca(2+) channel antagonist, 10 micro g/kg) inhibited acetylcholine release at 2 and 4 Hz by about 40%, norepinephrine release at 4 Hz by about 50%, and epinephrine release at 2 and 4 Hz by about 45%. A 5-fold higher dose of omega-conotoxin GVIA (50 micro g/kg) did not further inhibit these releases. omega-Conotoxin MVIIC (a P/Q-type Ca(2+) channel antagonist, 50 micro g/kg) inhibited acetylcholine and epinephrine releases at 4 Hz by about 30%. Combined omega-conotoxin GVIA (50 micro g/kg) and MVIIC (250 micro g/kg) inhibited acetylcholine release at 2 and 4 Hz by about 70%, norepinephrine and epinephrine releases at 2 and 4 Hz by about 80%. Nifedipine (an L-type Ca(2+) channel antagonist, 300 and 900 micro g/kg) did not change acetylcholine release at 2 and 4 Hz, but nifedipine (300 micro g/kg) inhibited epinephrine release at 4 Hz by 20% and nifedipine (900 micro g/kg) inhibited norepinephrine and epinephrine releases at 4 Hz by 30%. In conclusion, both N- and P/Q-type Ca(2+) channels control acetylcholine release on pre-ganglionic splanchnic nerve endings while L-type Ca(2+) channels do not. L-type Ca(2+) channels are involved in norepinephrine and epinephrine releases on chromaffin cells.

Alam, M., and Thomson, R.H. (1997) Handbook of natural products from marine invertebrates, Part 1 Phylum Mollusca. by Maktoob Alam and Ronald H. Thomson
ISBN 90-5702-253-2 Subtitle (phylum Mollusca) Publisher Harwood Academic Publishers, Amsterdam, 1997 Subject Marine invertebrates -- Handbooks, manuals, etc. Publication Date 1997. Illustrations Yes
Abstract: A listing of hundreds of compounds derived from members of the phyllum Mollusca. Includes terpenes, polypropionates, aromatic and aliphatic nitrogenous compounds, polypeptides, macrolides, prostaglandins, and sterols. Each entry includes a molecular formula, the scientific and trivial name (if any) of the compound, the source mollusk, bioactivity information, reference sources, and more. The review copy contained two tables of contents but not the preface that appears in the table of contents. Entries are indexed by source, name, and molecular formula.
UniM, Chem, 572.3613,MAKT

Albillos A, García AG, Olivera BM, Gandía L (1996) Re-evaluation of the P/Q Ca 2+ channel components of the Ba 2+ currents in bovine chromaffin cells superfused with solutions containing low and high Ba 2+ concentrations. Pflügers Arch 432 1030–1038
Key words: Calcium channels, Chromaffin cells, w-agatoxin IVA, w-Conotoxin GVIA, w-Conotoxin MVIIC, Furnidipine.

Alcala, A.C. (1983) Recent cases of crab, cone shell, and fish intoxication on Southern Negros Island, Philippines. Toxicon, suppl. 3, 1.

Alexander,C.G. (1971a). The osphradium of Conus flavidus. Marine Biology. 6 (3). 236-240

Alexander,C.G. (1973). The neuroanatomy of the osphradium in Conus flavidus Lamarck. The Veliger. 16 (1). 68-71

Alexander,C.G. & Weldon,M.W. (1975). The fine structure of the osphradial leaflets in Conus flavidus Marine Biology, 33: 247-254

Alonso D., Khalil Z., Satkunanathan N. and Livett B.G. (2003) Drugs From the Sea: Conotoxins as Drug Leads for Neuropathic Pain and Other Neurological Conditions. Mini Reviews in Medicinal Chemistry 3: 785-787
Abstract:The oceans are a source of a large group of structurally unique natural products that are mainly found in invertebrates such as sponges, tunicates, bryozoans, and molluscs. It is interesting to note that the majority of marine compounds currently in clinical trials or under preclinical evaluation are produced by these species rather than as secondary metabolites by marine algae [1]. Through the combined efforts of marine natural products chemists and pharmacologists a number of promising compounds have been identified that are either already at advanced stages of clinical trials such as the new anti-cancer drug marine alkaloid ecteinascidin 743 [2], or have been selected as promising candidates for extended preclinical evaluation [3]. This is the case for conotoxins, (Table 1) where a number of conopeptides are currently being developed as analgesics for the treatment of neuropathic pain. PMID: 14529519 [PubMed - in process]

Azuma, (1973). On the radulae of some remarkable gastropods from off Kirimezaki, Kii Peninsula, Japan, with the description of a new cone shell. 8pp., 1pl., 11figs., in Japanese & English, with message from author. Euro 1.50

Baell JB, Harvey AJ, Norton RS. (2002) Design and synthesis of type-III mimetics of ShK toxin. J Comput Aided Mol Des. 16 : 245-62.
Abstract:ShK toxin is a structurally defined, 35-residue polypeptide which blocks the voltage-gated Kv1.3 potassium channel in T-lymphocytes and has been identified as a possible immunosuppressant. Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. ShK toxin is a challenging target for mimetic design as its binding epitope consists of relatively weakly binding residues, some of which are discontinuous. We discuss here our investigations into the design and synthesis of 1st generation, small molecule mimetics of ShK toxin and highlight any principles relevant to the generic design of type-III mimetics of continuous and discontinuous binding epitopes. We complement our approach with attempted pharmacophore-based database mining.

Bandyopadhyay, P.K., Colledge, C.J., Walker, C.S., Zhou, L., Hillyard, D.R., Olivera, B.M. (1998) Conantokin-G precursor and its role in g -carboxylation by a vitamin K-dependent carboxylase from a Conus snail. JBC 273: 5447-5450.

BALL, 2002. Foregut ontogeny of the Neogastropoda: comparison of development in Nucella lapillus & Conus anemone. 28pp., 19figs., 2tabs..

Bandel, 1984. The radulae of Caribbean & other Mesogastropoda & Neogastropoda. 188pp., 22pls., 346figs., .

Bandel & al., 1977. On Conus mediterraneus & C. guinaicus. 13pp., 31figs., Dutch summ., with message from the 2nd author. Euro 1.95

Banos J.E., Sanchez G., Berrendero F. and Maldonado R. (2003) Neuropathic Pain: Some Clues for Future Drug Treatments. Mini Reviews in Medicinal Chemistry 3: 719-727
Abstract:Neuropathic pain is still far from being adequately dealt with. Under this name, several clinical entities have been considered and most of them only share several painful ailments. At present, the available treatments can only alleviate the pain of roughly half of the patients, and their effectiveness is often limited by the appearance of the intolerable side effects. In this review, we will consider the pathophysiology of neuropathic pain to understand the basis of pharmacological treatments that are currently being investigated. Some examples of these drugs will also be considered. PMID: 14529513 [PubMed - in process]

Barabino, B., Vailati, S., Moretti, M., McIntosh, J.M., Longhi, R., Clementi, F. and Gotti, C. (2001) "An alpha 4beta nicotinic receptor subtype is present in chick retina. Identification, characterization and pharmacological comparison with the transfected alpha 4beta 4 and alpha 6beta 4 subtypes". Mol. Pharmacol. 59: (6) p. 1410-1417.

Barinaga, M. (1990). Science digests the secrets of voracious killer snails. Science.249: 250-251. [Extract: There are more than 500 species of cone shells, each with their own distinctive toxin. Scientists have found that these toxins are ideal substances with which to investigate the properties of nerve cell receptors and ion channels. Most exciting is the hope that cone-shell toxins can be used to unravel the properties of the NMDA receptor, which is implicated in learning and memory in humans (Barinaga, 1990)].

BARTSCH & al., 1943. New cones from the Hawaiian Isls. 4pp. Euro 0.70

Basus, V.J., Nadasdi, L., Ramachandran, J. and Miljanich, G.P. (1995) Solution structure of omega-conotoxin MVIIA using 2D NMR spectroscopy.FEBS Letters, 370: 163-170..
Abstract: The solution structure of omega-conotoxin MVIIA (SNX-111), a peptide toxin from the fish hunting cone snail Conus magus and a high-affinity blocker of N-type calcium channels, was determined by 2D NMR spectroscopy. The backbones of the best 44 structures match with an average pairwise RMSD of 0.59 angstroms. The structures contain a short segment of triple-stranded beta-sheet involving residues 6-8, 20-21, and 24-25. The structure of this toxin is very similar to that of omega-conotoxin GVIA with which is has only 40% sequence homology, but very similar calcium channel binding affinity and selectivity.

BAYER, F.M. & G.L. VOSS (EDS), 1971. Studies in Tropical American Mollusks; [6], 236 p., 207 figs, cloth (library stamp). Contains 4 papers: Cephalopods Collected in the Gulf of Panama / Mollusks from the Gulf of Panama / The Conidae of the Pilssbury Expedition / New and Unusual Mollusks Collected.

BENTHEM JUTTING, T. VAN, 1932-1960.Sammlung nichtmariner Mollusken aus dem niederschlagsarmen Gebiete Nordost-Brasiliens. ML03255 € 22,00
Collection of 5 papers on marine molluscs; Includes two papers on shells from prehistoric kitchen-middens, one on Conus nobilis, one on Quartenary shells from Venezuela, and one on malacological research in the Malay Archipelago.

Bhakuni, D.S. (1995) The toxic metabolites of marine organisms. J. Scientific & Industrial Research. 54 (12): 702-716. [Abstract: The toxic metabolites of diatoms, blue-green algae, sea-cucumber, sponges, coelenterate, and tunicates have been reviewed. The origin, biosynthesis, mechanism of action of saxitoxin, tetrodotoxin, brevetoxins, palytoxin and their derivatives, ciguatoxins, maitotoxin, diarrhetic shellfish toxins, pectenotoxins, yessotoxin, neosuruatoxin, and prosurugatoxin have been discussed. Cone shell and sea snake venoms have also been reviewed]. [References: 139]

Dunlap ME, Bibevski S, Rosenberry TL, Ernsberger P. (2003) Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity. Am J Physiol Heart Circ Physiol. 285: H1632-40.

Bibevski S, Zhou Y, McIntosh JM, Zigmond RE, Dunlap ME. (2000) Functional nicotinic acetylcholine receptors that mediate ganglionic transmission in cardiac parasympathetic neurons. J Neurosci. 20: 5076-82.
Abstract: Nicotinic acetylcholine receptors (nAChRs) mediate ganglionic transmission in the peripheral autonomic nervous system in mammals. Functional neuronal nAChRs have been shown to assemble from a combination of alpha and beta subunits, including alpha3, alpha5, alpha7, beta2, and beta4 in RNA-injected oocytes, but the subunit composition of functional neuronal nAChRs in vivo in mammals remains unknown. We examined the subunit composition of functional nAChRs in the intracardiac parasympathetic ganglion in a physiologically intact system in vivo. We report here that localized perfusion of the canine intracardiac ganglion in situ with an antagonist specific for nAChRs containing an alpha3/beta2 subunit interface (alpha-conotoxin MII 100-200 nm) resulted in reversible attenuation of the sinus cycle length (SCL) response by approximately 70% to electrical stimulation of the preganglionic vagus nerve. Perfusion with antagonist specific for receptors containing an alpha3/beta4 subunit interface (alpha-conotoxin AuIB 1 micrometer) resulted in attenuation in SCL responses (approximately 20%) compared with baseline when applied by itself, but not in animals pretreated with alpha-conotoxin MII. Perfusion of the ganglion with alpha-bungarotoxin (1 micrometer, which blocks alpha7 receptors) caused a reduction in SCL response by approximately 30% compared with baseline when perfused on its own and when added after blockade with MII and AuIB. Perfusion with hexamethonium bromide resulted in complete blockade of ganglionic transmission, confirming total perfusion of the ganglion and the nicotinic nature of ganglionic transmission at this synapse. Immunohistochemistry using monoclonal antibodies against specific nicotinic subunits confirmed the presence of alpha3, alpha7, beta2, and beta4 subunits. We conclude that functional ganglionic transmission in the canine intracardiac ganglion is mediated primarily by receptors containing an alpha3/beta2 subunit interface, with a smaller contribution by receptors containing alpha7 nAChRs. Despite the presence of beta4 subunits in functional channels, a contribution of a distinct alpha3/beta4 receptor population that does not include an alpha3/beta2 subunit interface was less clear.

Bibevski S, Dunlap ME. (1999) Ganglionic mechanisms contribute to diminished vagal control in heart failure. Circulation. 99:2958-63.

Bingham, J-P., Jones, A., Lewis, R.J., Andrews, P.R. and Alewood, P.F. (1996) Conus venom peptides (Conopeptides) Inter-Species, intra-species and within individual variation revealed by ionspray mass spectrometry. Chapter 2, In Lazarovici P, Spira ME, Zlotkin, E, (Eds), Biochemical Aspects of Marine Pharmacology, Alaken Inc. Fort Collins Colorado, Proceedings of Eilat Conference on Interuniversity Institute of Marine Sciences Eilat, May, 1995, pp. 13-27. [Abstract: This manuscript provides an overview of the mass spectrometric studies of cone shell venoms that the Alewood group is currently conducting as part of a search for new bioactive conopeptides and, ultimately, novel peptidomimetic drugs. These studies reveal surprising variability in the molecular composition of Conus toxins both between and within species, and even within individual specimens].

Boccaccio, A., Conti, F., Olivera, B.M. and Terlau, H. (2004) Binding of {kappa}-Conotoxin PVIIA to Shaker K+ Channels Reveals Different K+ and Rb+ Occupancies within the Ion Channel Pore. J. Gen. Physiol. 124: 71-81.

BOZZETTI, 2004. Conus solangeae dal Madagascar Meridionale. 2pp., 1tab., 7col.figs. MALACOLOGICA MOSTRA MONDIALE, 43 [2004]. 16ppEuro 10.0

BOZZETTI, 2005. Conus giorossii sp.n. da Flores, Indonesia. 3pp.,

Brown, M,A., Hambe, B., Furie, B., Furie, B.C., Stenflo, J. and Stenberg, L.M.(2002) Detection of vitamin K-dependent proteins in venoms with a monoclonal antibody specific for gamma-carboxyglutamic acid. Toxicon, 40: 447-454. .
Abstract: gamma-Carboxyglutamic acid (Gla) is an unusual amino acid that is synthesized post-translationally from glutamate in a vitamin K-dependent reaction. The dicarboxylic side chain of Gla chelates Ca2+, a property important for the biological activity of vitamin K-dependent proteins. To date, Gla-containing polypeptides have been identified in venom from two groups of organisms: elapid snakes, and snails of the genus Conus. In certain elapid snakes, a gamma-carboxylated coagulation factor Xa-like protein is a component of the venom whereas cone snails utilize Gla in a range of peptide neurotoxins. Using a monoclonal antibody that specifically recognizes Gla residues, venom samples from various organisms were screened by western blotting and immunofluorescence assays. Amino acid analyses were also performed on most samples. A survey of 21 snake species from 12 genera detected gamma-carboxylated polypeptides only in venom of snakes from the elapid subfamily Acanthophiinae. Gla-containing polypeptides were also observed in cone snail venom but not in venom or toxic salivary secretions from several other organisms. The Gla-specific antibody used here provides a simple immunochemical means to detect gamma-carboxylated polypeptides in venom and may allow new species to be identified that utilize Gla in the biosynthesis of toxic polypeptides.

Broxton, N.M., Down, J.G., Gehrmann, J., Alewood, P.F., Satchell, D.G. and Livett, B.G. "Alpha-conotoxin ImI inhibits the alpha-bungarotoxin-resistant nicotinic response in bovine adrenal chromaffin cells". J. Neurochem. 72:1656-1662 (1999).
Abstract: Reference concerning the selectivity of conotoxin ImI from Conus imperialis for the neuronal-type nicotinic receptor.

. Buccafusco, J.J.(2004) Neuronal Nicotinic Receptor Subtypes: DEFINING THERAPEUTIC TARGETS. Mol Interv. 4:285-295.
Alzheimer's Research Center, Medical College of Georgia, 1120 15 Street, Augusta, Georgia 30912-2300.

Abstract:Humans have appreciated the beneficial properties of the tobacco plant for thousands of years. These effects include alertness, reduced anxiety, muscle relaxation, and analgesia. Yet it has been less than two decades since the central actions of nicotine have been examined in earnest for potential therapeutic applications. In fact, the cholinergic systems, in comparison to other neurotransmitter systems of the body, have been relatively poorly exploited in terms of therapeutic agents, and the muscarinic cholinergic systems have been relegated mainly to the treatment of gastrointestinal disorders and glaucoma; for the nicotinic system, antagonists are used to induce muscle paralysis during certain surgical procedures. For both families of cholinergic receptors, widespread exploitation in terms of therapeutics has been limited by significant side effect profiles associated with available cholinergic drugs.

Bulaj, G. Representative Publications

  • Buczek O, Olivera BM, Bulaj G "Propeptide Does not Act as an Intramolecular Chaperone, but Facilitates Protein Disulfide Isomerase - Assisted Folding of a Conotoxin Precursor" Biochemistry - in press
  • Bulaj G, Buczek O, Goodsell I, Jimenez EC, Kranski J, Nielsen JS, Garrett JE, Olivera BM (2003) "Efficient Oxidative Folding of Conotoxins and the Radiation of Venomous Cone Snails" Proc Natl Acad Sci USA, 100, Suppl 2, 14562-14568.

    Bulaj G, Buczek O, Goodsell I, Jimenez EC, Kranski J, Nielsen JS, Garrett JE, Olivera BM. (2003)Efficient oxidative folding of conotoxins and the radiation of venomous cone snails. Proc Natl Acad Sci U S A. 100 Suppl 2:14562-14568.
    Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.

    Abstract: The 500 different species of venomous cone snails (genus Conus) use small, highly structured peptides (conotoxins) for interacting with prey, predators, and competitors. These peptides are produced by translating mRNA from many genes belonging to only a few gene superfamilies. Each translation product is processed to yield a great diversity of different mature toxin peptides (approximately 50,000-100,000), most of which are 12-30 aa in length with two to three disulfide crosslinks. In vitro, forming the biologically relevant disulfide configuration is often problematic, suggesting that in vivo mechanisms for efficiently folding the diversity of conotoxins have been evolved by the cone snails. We demonstrate here that the correct folding of a Conus peptide is facilitated by a posttranslationally modified amino acid, gamma-carboxyglutamate. In addition, we show that multiple isoforms of protein disulfide isomerase are major soluble proteins in Conus venom duct extracts. The results provide evidence for the type of adaptations required before cone snails could systematically explore the specialized biochemical world of "microproteins" that other organisms have not been able to systematically access. Almost certainly, additional specialized adaptations for efficient microprotein folding are required.

  • Jones, R.M. and Bulaj, G. (2000)Conotoxins: New vistas for peptide therapeutics. Current Pharmaceutical Design August 2000 Volume 6 number 12, 1249-1285. Full article available.
  • Nielsen J, Buczek P, Bulaj G "Cosolvent-Assisted Oxidative Folding of a Bicyclic (-Conotoxin ImI" J Pept Science, in press
  • Keizer DW, West PJ, Lee EF, Yoshikami D, Olivera BM, Bulaj G, Norton RS (2003) "Structural basis for tetrodotoxin-resistant sodium channel binding by (delta-conotoxin SmIIIA" J Biol Chem, 278, 46805-46813
  • Dela Cruz R, Whitby F, Buczek O, Bulaj G (2003) "Detergent-assisted oxidative folding of omega-Conotoxins" J Pept Research 61, 202-212
    Abstract:Conotoxins comprise a diverse group of disulfide-rich peptides found in venoms of predatory Conus species. The native conformation of these peptides is marginally stable in comparison with alternative conformations, often resulting in low folding yields. The oxidative folding of hydrophobic delta-conotoxins was found to produce less than 1% of the native peptide [Bulaj, G. et al. (2001) Biochemistry 40, 13201]. In order to identify factors that might improve folding yields, we screened a number of additives including water-soluble polymers, detergents and osmolytes for their ability to increase steady-state accumulation of the native delta-conotoxin PVIA. The presence of a non-ionic detergent Tween and low temperature appeared to be the most effective factors in improving the oxidative folding. The detergent was also effective in promoting folding of other hydrophobic delta-conotoxins. Based on our findings, we discuss a possible mechanism for detergent-assisted folding and the general applicability of this mechanism to facilitating the proper folding of hydrophobic, cysteine-rich peptides.
  • West PJ, Bulaj G, Garrett JE, Olivera BM, Yoshikami D. (2002) "(delta-Conotoxin SmIIIA, a Potent Inhibitor of Tetrodotoxin-Resistant Sodium Channels in Amphibian Sympathetic and Sensory Neurons" Biochemistry 41, 15388-15393
  • Miles LA, Dy CY, Nielsen J, Barnham KJ, Hinds MG, Olivera BM, Bulaj G, Norton RS. (2002) "Structure of a novel P-superfamily spasmodic conotoxin reveals an inhibitory cystine knot motif" J Biol Chem 277, 43033-40

    Castellino, F.J. and Prorok, M. (2000) Conantokins: Inhibitors of ion flow through the N-Methyl-D-Aspartate receptor channels Current Drug Targets 1: 230-235.
    Full text
    Abstract:Calcium flow through the ion channel of the N-methyl-D-aspartate receptor (NMDAR) has been implicated as contributing to a variety of neuropathologies. This receptor is a complex heteromeric oligomer consisting of different types of subunits, the nature of which governs its properties, as well as its response to a variety of agonists, antagonists, and other types of inhibitors. A new natural series of NMDAR inhibitors, the conantokins, have been shown to be present in the venoms of snails within the genus, Conus. These agents appear to function by inhibition of the spermine/spermidine stimulation of ion flow through the NMDAR channel. These small peptides (17-27 amino acid residues) are highly processed post-translationally. One such processing event is the vitamin K-dependent gamma-carboxylation of glutamate, resulting in placement of gamma-carboxyglutamic acid residues in these peptides. As a result, these peptides then possess the ability to interact with divalent metal ions and concomitantly undergo a conformational alteration. Rational drug design based on the characteristics of these promising peptides requires knowledge of their properties and the manner in which they target the NMDAR. This review summarizes current knowledge in this area.

    See also Prorok, M. and Castellino, F.J. (2001)Structure-Function Relationships of the NMDA Receptor Antagonist Conantokin Peptides. Current Drug Targets 2: 313-321. or (Full text)

    Steven G. Charapata and David Ellis (2002) Unintentional overdose with intrathecal ziconotide.Pain Medicine 3:(2) 189-190.
    Abstract:Ziconotide is a novel, N-type, voltage-sensitive calcium channel (VSCC) blocker, with well-documented efficacy as an intrathecal (IT) analgesic. Ziconotide has been administered to over 1000 chronic pain patients in nine clinical trials. Over 350 patients have been on ziconotide IT therapy for more than three months in a long-term safety and tolerability study. Common adverse events for ziconotide include dizziness, nausea, nystagmus, abnormal gait, constipation, urinary retention, somnolence, postural hypotension, vomiting, confusion and abnormal vision. Ziconotide adverse events are recognizable, reversible and manageable, by dose adjustment and slow dose titration. Case reports of unintentional overdose in six chronic pain patients treated with IT ziconotide are presented. These unintentional overdoses were attributable to pump programming or dilution errors; none were lethal. The patient who received the highest overdose was administered 31 mcg/hr over 24 hours, or nearly 750 mcg ziconotide, total. This hourly dose rate is 300-fold the current recommended initial dose rate of 0.1 mcg/hr. This patient was sedated, but arousable; vital signs were stable and patient had no change in blood pressure. His symptoms resolved within 24 hours. His Visual Analog Score of Pain Intensity (VASPI) was reduced from 82 at baseline to 2.5 at the end of the titration period. The patient elected to continue in the long-term IT ziconotide study. The other 5 cases of inadvertent overdose were less severe, with dose rate at 5 mcg/hr or less. Associated adverse events also resolved within 24-hours of discontinuing ziconotide infusion. Unlike an unintentional overdose with IT morphine, which slows respiration and could potentially lead to hypoxia, coma or death; ziconotide does not produce respiratory depression. No tolerance to the analgesic effect of ziconotide, or withdrawal symptoms after discontinuation of the drug have been reported. Ziconotide has a wide margin of safety as an IT analgesic.

    Cai Yingya (2002) Marine Mollusca of Guangdong 2. 94pp., figs., in Chinese softcover, Small size: 185x115mm. ISBN: 7-81036-098-1 (Euro 8.00)
    Abstract: This guide deals with 125 species from the families Muricidae, Columbellidae, Buccinidae, Galeodidae, Nassariidae, Fasciolariidae, Olividae, Mitridae, Harpidae, Volutidae, Cancellariidae, Marginidae, Conidae, Turridae, Terebridae, Architectonidae, Janthinidae and Epitoniidae.

    Cho, C.H., Song, W., Leitzell, K., Teo, E., Meleth, A.D., Quick, M.W. and Lester, R.A. (2005) Rapid upregulation of alpha7 nicotinic acetylcholine receptors by tyrosine dephosphorylation. J. Neurosci. 25: 3712-3723.
    Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0021, USA.

    Abstract: Alpha7 nicotinic acetylcholine receptors (nAChRs) modulate network activity in the CNS. Thus, functional regulation of alpha7 nAChRs could influence the flow of information through various brain nuclei. It is hypothesized here that these receptors are amenable to modulation by tyrosine phosphorylation. In both Xenopus oocytes and rat hippocampal interneurons, brief exposure to a broad-spectrum protein tyrosine kinase inhibitor, genistein, specifically and reversibly potentiated alpha7 nAChR-mediated responses, whereas a protein tyrosine phosphatase inhibitor, pervanadate, caused depression. Potentiation was associated with an increased expression of surface alpha7 subunits and was not accompanied by detectable changes in receptor open probability, implying that the increased function results from an increased number of alpha7 nAChRs. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated exocytosis was shown to be a plausible mechanism for the rapid delivery of additional alpha7 nAChRs to the plasma membrane. Direct phosphorylation/dephosphorylation of alpha7 subunits was unlikely because mutation of all three cytoplasmic tyrosine residues did not prevent the genistein-mediated facilitation. Overall, these data are consistent with the hypothesis that the number of functional cell surface alpha7 nAChRs is controlled indirectly via processes involving tyrosine phosphorylation.

    Concar, D. (1996) Doctor snail. (cone snail venom) New Scientist, 152: 26-28. .
    Abstract: Filipino biochemist Baldomero Olivera and his colleagues at the University of Utah in Salt Lake City observed a variety of weird effects when toxins from cone snail venom were injected into the brains of laboratory mice. Cone snail venom contains hundreds, even thousands of toxins. Potential applications of snail toxins include the relief of serious pain, brain damage prevention, and the treatment of depression, epilepsy and schizophrenia.

    Coomans & al., 1979-86. "Alphabetical revision of the (sub) species in recent Conidae 1-9". 469pp., 760figs., in 9 issues. Hfl. 120.00

    Conticello, S. G., Pilpel, Y., Glusman, G. and Fainzilber, M. (2000) "Position-specific codon conservation in hypervariable gene families." Trends in Genetics 16:57-59 (2000).
    Abstract: Reference concerning of the third nucleotide (T or C) in two codons (TGT or TGC) that code for Cysteine. Analysis of cysteine codon usage in a number of hypervariable gene families revealed strict codon conservation in specific positions adjacent to or within the hypervariable regions of these genes. This phenomenon suggests the possible existence of specific positional codon-conservation mechanisms in certain genes. The phenomenon of position-specific codon conservation may provide a functional-genomics aproach to identify important residues for further structural and functional study. Moreover, this observation suggests that novel mechanisem could exist to conserve crucial resides in hypervariable gene families.

    Cartier, G.E., Yoshikami, D., Gray, W.R., Luo, S., Olivera, B.M. and McIntosh, M. (1996) A new alph-conotoxin which targets alpha3beta2 nicotinic acetylcholine. J. Biol. Chem. 271: 7522-7528.
    [Abstract:[Conus magus, alpha-conotoxin MII, 16aa peptide, blocks nAChR composed of alpha3beta2 subunits (IC50=0.5nM), some 2-4 orders of magnitude less potent against other subunit combinations, electrophysiology, Voltage clamp of Xenopus oocytes, venom extraction, RPLC purification, pyridylehthylation and RPLC purification, alpha 4-7 group, In vivo, in contrast to MI, MII had no effect i.p. in Swiss Webster mice or i.m. in goldfish; preferentially targets neuronal-type vs. muscle-type nAChRs]

    Chen, J.S., Fan, C.X., Hu, K.P., Wei, K.H. and Zhong, M.N.(1999) Studies on conotoxins of Conus betulinus. J. Nat. Toxins 8: 341-349.
    [Abstract:The biological activity and toxicity of crude venom from Conus betulinus, which was collected from the South China Sea, were studied. The venom shows Ach receptor activity, K+ current effect, and low toxicity. Four peptide components, named BeTXIa, BeTXIb, BeTXIIa, and BeTXIIb, were purified by gel-filtration with Sephadex followed by HPLC, and finally sequenced on an ABI model 491 sequencer. The low-molecular-weight peptides BeTXIa and b have 14 and 15 amino acid residues, respectively, while BeTXIIa and b have 27 and 30 amino acid residues, respectively. The results indicate that BeTXs from the venom of C. betulinus are a set of small peptides with a high cysteine content like known conotoxins. However, it is meaningful to find that these sequences have specific chemical characteristics in their cysteine framework which differ greatly from known cysteine frameworks in conotoxin structures.]

    Clench, W.J., Kondo, Y.(1943) The poison cone shell. Amer. J. Trop. Med. 23, 105-

    CLENCH & al., 1946. The Poison Cone Shell. 27pp., 5pls.

    Eugene V. Coan, Alan R. Kabat & Richard E. Petit (2004), "2,400 Years of Malacology," is online at http://erato.acnatsci.org/ams/publications/epubs.html

    This publication is a comprehensive catalog of biographical and bibliographical papers on malacologists, conchologists, paleontologists, and others with an interest in mollusks. At present, the catalog is over 600 pages and indexes over 5,000 individuals. This catalog is a work in progress, and we will be posting updated versions periodically. Readers are encouraged to explore and use this catalog, and to forward to their comments to the authors.

    Colledge, C.J., Hunsperger, J.P., Imperial J.S., Hillyard, D.R. (1992) Precursor structure of w -conotoxin GVIA determined from a cDNA clone. Toxicon 30: 1111-1116.

    COOMANS & al., 1979-86. Alphabetical revision of the (sub) species in recent Conidae 1-9. 469pp., 760figs., in 9 issues. Euro 56.00

    Craig. A.G., Jimenez, E.C., Dykert, J., Nielsen, D.B., Gulyas, J., Abogadie, F.C., Porter, J., Rivier, J.E., Cruz, L.J., Olivera, B.M. and McIntosh, M. (1997) A novel post-translational modification involving bromination of tryptophan - Identification of the residue, L-6-bromotryptophan, in peptides from Conus imperialis and Conus radiatus venom.J. Biol. Chem. 272, 4689-4698.
    [Abstract:[describes a novel post-translational modification (halogenation of tryptophan) of a heptapeptide isolated from the imperial cone, Conus imperialis, a worm-eating cone, and from a 33-amino acid peptide from the radial cone, Conus radiatus, a fish-eating cone. "The occurrence of 6-bromotryptophan in Conus peptides could be due to an adaptation involving the recruitment of an enzymatic system already generally distributed among marine organisms, the cone snails have used this more general bromination chemistry evolved in marine ecosystems in a specialized way in their venom ducts".]

    Craig, A. G., Norberg, T., Griffin, D., Hoeger, C., Akhtar, M., Schmidt, K., Low, W., Dykert, J., Richelson, E., Navarro, V., Mazella, J., Watkins, M., Hillyard, D., Imperial, J., Cruz, L. J., Olivera, B. M. (1999). "Contulakin-G, an O-Glycosylated Invertebrate Neurotensin" J. Biol. Chem. 274: 13752-13759.

    [Contulakin-G is a 16 amino acid O-linked glycopeptide (pGlu-Ser-Glu-Glu-Gly-Gly-Ser-Asn-Ala-Thr-Lys-Lys-Pro-Tyr-Ile-Leu-OH, pGlu is pyroglutamate) from Conus geographus, whose C-terminus resembles neurotensin. Causes motor control-associated dysfunction when injected into mice. The investigators conclude "that O-linked glycosylation appears to be a highly unusual strategy for increasing the efficacy of toxins directed against neurotransmitter receptors"].

    Costa, F.H.A. (1996) "Natural history and evolution patterns in Conus californicus Hinds in Reeve, 1844". La Conchiglia, Jan-March, pp. 44-52.
    [Abstract: Conus californicus: Most cones are crepuscular, but there is always an exception to the rule. A good example is Conus californicus which is durnal.]

    Cui C, Booker TK, Allen RS, Grady SR, Whiteaker P, Marks MJ, Salminen O, Tritto T, Butt CM, Allen WR, Stitzel JA, McIntosh JM, Boulter J, Collins AC, Heinemann SF. (2003) The beta3 nicotinic receptor subunit: a component of alpha-conotoxin MII-binding nicotinic acetylcholine receptors that modulate dopamine release and related behaviors. J Neurosci. 23: 11045-11053.

    Nigrostriatal dopaminergic neurons express many nicotinic acetylcholine receptor (nAChR) subunits capable of forming multiple nAChR subtypes. These subtypes are expressed differentially along the neuron and presumably mediate diverse responses. beta3 subunit mRNA has restricted expression but is abundant in the substantia nigra and ventral tegmental areas. To investigate the potential role(s) of nicotinic receptors containing the beta3 subunit in dopaminergic tracts, we generated mice with a null mutation in the beta3 gene. We were thereby able to identify a population of beta3-dependent alpha-conotoxin MII-binding nAChRs that modulate striatal dopamine release. Changes were also observed in locomotor activity and prepulse inhibition of acoustic startle, behaviors that are controlled, in part, by nigrostriatal and mesolimbic dopaminergic activity, respectively, suggesting that beta3-containing nAChRs modulate these behaviors.

    Craig, A.G., Park, M., Fischer, W.H., Kang, J., Compain, P. and Piller, F. (2001) Enzymatic glycosylation of contulakin-G, a glycopeptide isolated from Conus venom, with a mammalian ppGalNAc-transferase. Toxicon, 39: 809-817..
    Abstract: We have determined that the mammalian uridine diphospho-N-acetyl-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase T1 (EC 2.4.1.41) has the appropriate acceptor substrate specificity to recognize the non-glycosylated form of contulakin-G (ZSEEGGSNATKKPYIL-OH where Z=pyroglutamic acid) and to transfer GalNAc to the peptide. Both [Thr10] contulakin-G and a pre-contulakin-G30-66 (RGLVPDDITPQLILGSLISRRQSEEGGSNATKKPYIL-OH) were shown to be acceptors for the mammalian enzyme. The site of attachment of the GalNAc residue was determined using chemical and radioactive sequencing techniques. The mammalian enzyme was highly specific for Thr10 residue, in which the native peptide was found to be glycosylated, compared with either Ser2 or Ser7. In the case of pre-contulakin-G, the enzyme was also highly specific for the equivalent threonine residue. These results suggest that the Cone snail uses an enzyme with similar acceptor specificity to that of the mammalian polypeptide N-acetylgalactosaminyltransferase for glycosylating contulakin-G.

    Craig, A.G., Zafaralla, G., Cruz, L.J., Santos, A.D., Hillyard, D.R., Dykert, J., J.E., Gray, W.R., Imperial, J., DelaCruz, R.G., Sporning, A., Terlau, H., West, P.J., Yoshikami, D. and Olivera, B.M. (1998) An O-glycosylated neuroexcitatory Conus peptide.Biochemistry,37: 16019-16026..
    Abstract: A study was conducted to describe a unique peptide resulting from the venom of the fish-hunting cone snail Conus striatus. An analytical Vydac C18 column was utilized to purify crude venom extract while lyophilized venom was suspended in an acetic acid solution. Experimental results indicated that the venom, which generates spastic paralysis in fishes, features several biochemical and physiological properties.

    Cruz, L.Z., Gray, W.R. and Olivera, B.M. (1978) Purification and properties of a myotoxin from Conus geographus. Archs. Biochem. Biophys. 190: 539-548.
    [Abstract:[ Conus geographus, paralysis of respiratory muscles in mice]

    Cruz, L.J. and White, J. (1995) Clinical toxicology of Conus snail stings. In : Meier, J., White, J. (Eds.) Clinical Toxicology of Animal Venoms. CRC Press, Boca Raton, FL. p. 117.

    Cruz, LJ and Jimenez, EC (2004) Conus venom neuropeptides Encyclopedia of Neuroscience 3rd Edition, Edited by George Adelman and Barry H. Smith, CD-ROM,p.291 ISBN: 0444514325, Elsevier, BV.
    Includes video clip showing envenomation of a small fish by a piscivorous cone shell.

    Currie BJ. (2000) Clinical toxicology: a tropical Australian perspective. Ther Drug Monit. 22 : 73-78. Tropical Medicine and International Health Unit, Menzies School of Health Research, Darwin, Northern Territory, Australia.
    Abstract: Tropical Australia has an amazing diversity of venomous fauna, from "the world's most venomous creature," the multi-tentacled (chirodropid) box jellyfish Chironex fleckeri, to aggressive spiders whose venom remains to be characterized. All genera of highly venomous Australasian elapid snakes are present, except for tiger snakes. Most notable is the taipan (Oxyuranus scutellatus), with the most efficient "snap-release" biting mechanism of any snake and venom components causing the full constellation of clinical envenoming features: coagulopathy from fibrinogen depletion (procoagulant), neurotoxicity (predominantly presynaptic neurotoxin) and rhabdomyolysis (myotoxin). Brown snakes (Pseudonaja textilis and P. nuchalis) now account for most snake bite fatalities in Australia, as a result of severe coagulopathy and a poorly defined early scenario of collapse, postulated to be caused by profound hypotension caused by transient myocardial dysfunction associated with prothrombin activation. Other venomous entities include paralyzing ticks, the blue-ringed octopus, stone fish and other marine animals with venomous spines, paralyzing cone shells, and a wide range of jellyfish including Carukia barnesi and possibly other four-tentacled (carybdeid) box jellyfish causing the Irukandji syndrome.

    Currie BJ. (2003) Marine antivenoms. J Toxicol Clin Toxicol. 41: 301-308.
    Tropical Medicine and International Health Unit, Menzies School of Health Research, Darwin, Northern Territory, Australia. bart@menzies.edu.au
    Abstract There is an enormous diversity and complexity of venoms and poisons in marine animals. Fatalities have occurred from envenoming by sea snakes, jellyfish, venomous fish such as stonefish, cone snails, and blue-ringed octopus. Deaths have also followed ingestion of toxins in shellfish, puffer fish (Fugu), and ciguatoxin-containing fish. However antivenoms are generally only available for envenoming by certain sea snakes, the major Australian box jellyfish (Chironex fleckeri) and stonefish. There have been difficulties in characterizing the toxins of C. fleckeri venom, and there are conflicting animals studies on the efficacy of C. fleckeri antivenom. The vast majority of C. fleckeri stings are not life-threatening, with painful skin welts the major finding. However fatalities that do occur usually do so within 5 to 20 minutes of the sting. This unprecedented rapid onset of cardiotoxicity in clinical envenoming suggests that antivenom may need to be given very early (within minutes) and possibly in large doses if a life is to be saved. Forty years of anecdotal experience supports the beneficial effect of stonefish antivenom in relieving the excruciating pain after stonefish spine penetration. It remains uncertain whether stonefish antivenom is efficacious in stings from spines of other venomous fish, and the recommendation of giving the antivenom intramuscularly needs reassessment.

    Dall, (1911). Summary of the shells of the genus Conus from the Pacific coast of America in the U.S.N.M. 12pp.

    Daly NL, Ekberg JA, Thomas L, Adams DJ, Lewis RJ, Craik DJ. (2004) Structures of mu O-conotoxins from Conus marmoreus: Inhibitors of TTX-sensitive and TTX-resistant sodium channels in mammalian sensory neurons. J Biol Chem. 2004 Mar 24 [Epub ahead of print]

    Centre for Drug Design and Development, Institute for Molecular Bioscience, Brisbane, QLD 4072.
    The muO-conotoxins are an intriguing class of conotoxins targeting various voltage-dependent sodium channels and molluscan calcium channels. In the current study, we have shown MrVIA and MrVIB to be the first known peptidic inhibitors of the transient tetrodotoxin-resistant (TTX-R) Na+ current in rat dorsal root ganglion neurons, in addition to inhibiting tetrodotoxin-sensitive Na+ currents. Human TTX-R sodium channels are a therapeutic target for indications such as pain, highlighting the importance of the muO-conotoxins as potential leads for drug development. Furthermore, we have used NMR spectroscopy to provide the first structural information on this class of conotoxins. MrVIA and MrVIB are hydrophobic peptides that aggregate in aqueous solution but were solubilized in 50% acetonitrile/water. The three-dimensional structure of MrVIB consists of a small betasheet and a cystine knot arrangement of the three-disulfide bonds. It contains four backbone loops between successive cysteine residues that are exposed to the solvent to varying degrees. The largest of these, loop 2, is the most disordered part of the molecule, most likely due to flexibility in solution. This disorder is the most striking difference between the structures of MrVIB and the known delta- and omega-conotoxins, which along with the muO-conotoxins are members of the O superfamily. Loop 2 of omega-conotoxins has previously been shown to contain residues critical for binding to voltage-gated calcium channels and it is interesting to speculate that the flexibility observed in MrVIB may accommodate binding to both sodium and molluscan calcium channels.

    DAUTZENBERG, PH. ET AL., 1935-1939. Résultats Scientifiques du Voyage aux Indes Orientales Néerlandaises. Vol. II. Deuxičme partie. Gastérapodes marins. 1. Terebridae. 2. Mitridae. 3. Conidae. Prosobranchia et Opisthobranchia. Gastropoda-Pulmonata, Scaphopoda et Bivalvia; 827 p., num. figs, 22 (9 col.) pls, paperbound. Unopened copy. Published in: Mémoires du Musée royal d'Histoire Naturelle.

    (DAUTZENBERG, 1935) : Résultats Scientifiques du Voyage aus Indes Orientales Néerlandaises de LL. AA. RR. le Prince & la Princesse Léopold de Belgique; containing: DAUTZENBERG, 1935. 2(17). Gastéropodes marins. 1. Familie Terebridae.&:

    DAUTZENBERG, 1935. Résultats Scientifiques du Voyage aus Indes Orientales Néerlandaises de LL. AA. RR. le Prince & la Princesse Léopold de Belgique, 2(18). Gastéropodes marins. 3. Familie Conidae. 282pp., 3colour pls., cover poor, some staining.

    DAUTZENBERG, PH., 1937. Résultats Scientifiques du Voyage aux Indes Orientales Néerlandaises. Gastérapodes marins. 3. Conidae; 284 p., 3 col. pls, roy. 4to, paperbound. Unopened copy. Published in: Mémoires du Musée royal d'Histoire Naturelle.

    DAUTZENBERG, P.(1978) 1. Gastéropodes Marins. 1. Famille Terebridae; 2. Famille Mitridae; 3. Famille Conidae. by DAUTZENBERG, P. Bruxelles 1935-37. 2 volumes. 4to. pp. 208; 284, with 7 coloured plates. Green half morocco, richly gilt spines. Published as parts of 'Résultats scientifiques du Voyage aux Indes Orientales Néerlandaises de LL. AA. RR. le Prince et la Princesse Léopold de Belgique' by V. Van Staelen. (Keywords MOLLUSCA DUTCH EAST INDIES)
    [Abstract:[Interesting book on conidae]

    DAVOLI, 1972. Studi monografici sulla malacologia miocenica modenese 1. - I Molluschi Tortoniani di Montegibbio [Gastropoda (seguito): fam. Conidae]. 104pp., 9pls., 40figs., 24tabs., English summ.

    Decker MW, Meyer MD, Sullivan JP. (2001) The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control. Expert Opin Investig Drugs. 2001 Oct;10(10):1819-1830
    Dept. 4N5, Building AP-9A/3, 100 Abbott Park Rd., Abbott Park, IL 60064-6125, USA. michael.w.decker@abbott.com
    Due to the limitations of currently available analgesics, a number of novel alternatives are currently under investigation, including neuronal nicotinic acetylcholine receptor (nAChR) agonists. During the 1990s, the discovery of the antinociceptive properties of the potent nAChR agonist epibatidine in rodents sparked interest in the analgesic potential of this class of compounds. Although epibatidine also has several mechanism-related toxicities, the identification of considerable nAChR diversity suggested that the toxicities and therapeutic actions of the compound might be mediated by distinct receptor subtypes. Consistent with this view, a number of novel nAChR agonists with antinociceptive activity and improved safety profiles in preclinical models have now been identified, including A-85380, ABT-594, DBO-83, SIB-1663 and RJR-2403. Of these, ABT-594 is the most advanced and is currently in Phase II clinical evaluation. Nicotinically-mediated antinociception has been demonstrated in a variety of rodent pain models and is likely mediated by the activation of descending inhibitory pathways originating in the brainstem with the predominant high-affinity nicotine site in brain, the alpha4beta2 subtype, playing a critical role. Thus, preclinical findings suggest that nAChR agonists have the potential to be highly efficacious treatments in a variety of pain states. However, clinical proof-of-principle studies will be required to determine if nAChR agonists are active in pathological pain.

    DELSAERDT, 1990. Conus visseri a n.sp. from Phuket Isl. Note on C. coffeae. 4pp., 10figs., Dutch summ.

    DELSAERDT, 1990. Complementary information concerning Conus lemuriensis & C. milneedwardsi. 2pp., 1fig., in English & Dutch. Euro 0.50

    DELSAERDT, 1990. Conus visseri a n.sp. from Phuket Isl. Note on C. coffeae. 4pp., 10figs., Dutch summ. Euro 0.60

    DODGE, H., 1953. A Historical Review of the Mollusks of Linneaus. Part 2. The Class Cephalopoda and the Genera Conus and Cypraea of the Class Gastropoda; 134 p., paperbound. Published in: Bulletin of the American Museum of Natural History.

    Doughty, S.W., Blaney, F.E., Orlek, B.S., Richards, W.G.(1998) A molecular mechanism for toxin block in N-type calcium channels. Protein Eng 11: 95-99.

    Duda, T.F., Jr. and Rolán, E. (2004). Explosive radiation of Cape Verde Conus, a marine species flock. Molecular Ecology (in press).

    Duda, T.F., Jr., Kohn, A.J. (2004). Species-level phylogeography and evolutionary history of the hyperdiverse marine gastropod genus Conus. Molecular Phylogenetics and Evolution (in press).

    Duda Jr TF, Palumbi SR. (2004) Gene expression and feeding ecology: evolution of piscivory in the venomous gastropod genus Conus. Proc R Soc Lond B Biol Sci. 271: 1165-1174.
    Naos Marine Laboratory, Smithsonian Tropical Research Institute, Box 2072, Balboa, Ancon, Republic of Panama.
    Abstract: Differential expression of gene-family members is typically associated with the specific development of certain tissues and organs, but its importance in the ecological adaptation of organisms has rarely been investigated. Several specialized feeding modes have evolved within the predatory marine gastropod genus Conus, including molluscivory and piscivory. Based on phylogenetic investigations of Conus species, it has been concluded that piscivory arose at least twice in this genus. Moreover, molecular analyses of conotoxin mRNA transcripts reveal that piscivores from independent evolutionary lineages express the same subset of four-loop conotoxins, contrary to phylogenetic expectations. These results demonstrate that differential expression of gene-family members can play a key role in adaptive evolution, particularly during shifts to new ecological niches.

    Duda Jr TF, Jon-Paul Bingham, Bruce G. Livett, Alan J. Kohn, Gabriella Raybaudi Massilia, Joseph R. Schultz, John Down, David Sandall and Jonathan V. Sweedler; and Mike Fainzilber (2004) How Much at Risk Are Cone Snails? ;Response: Eric Chivian, Callum M. Roberts and Aaron S. Bernstein Science 303: (Feb 13 2004) 955-957.

    Ekberg, J.A., Adams, D.J., Mould, J., Baker, M.D., Wood, J.N. and Lewis, R.(2005) The µO-conotoxin MrVIB selectively inhibits the TTX-resistant voltage-sensitive sodium channel Nav1.8 but not Nav1.9. Proc. 25th Annual Meeting, Australian Neuroscience Society. Perth, 25 January-2 February 2005, POS-MON-092

    Eichorn, A.(1916) - Die Herstellung von Muschelperlen aus Conus auf der Insel Ponam und ihre Verwendung im Kunsthandwerk der Admiralitaetsinsulaner. Baessler-Archiv, Vol. V, No. 6, 1916, pp. 256-283.

    Eldabe, S. (2007) Ziconotide: a new option for intrathecal analgesia. Future Neurology, January 2007, Vol. 2, No. 1, Pages 11-19.
    Consultant in Anaesthesia & Pain Management, The James Cook University Hospital, Middlesbrough, TS4 3BW, UK.


    Abstract:Ziconotide is the synthetic equivalent of a neuroactive peptide found in the venom of the fish-hunting marine snail Conus magus. Its analgesic effect is mediated by a blockade of the N-type calcium channel in the dorsal horn of the spinal cord. The drug is currently licensed for continuous intrathecal infusion in the treatment of chronic intractable pain, and its analgesic efficacy has been demonstrated in both animal and human studies. Ziconotide-induced analgesia is not associated with the development of tolerance, respiratory depression or endocrine side effects, as is common in opioids. Ziconotide is a potent analgesic with a narrow therapeutic window. A low starting dose with slow upward titration, while monitoring the patient, is the recommended strategy for avoiding the more serious side effects, such as delirium, acute psychotic reactions, suicidal ideation and coma.

    Rachid El Kouhen, Carol S Surowy, Bruce Bianchi, Torben Neelands, Heath McDonald, Wende Niforatos, Arthur Gomtsyan, Chih-Hung Lee, Prisca Honore, James Sullivan, Michael Jarvis, and Connie Faltynek (2005) A-425619, a Novel and Selective TRPV1 Receptor Antagonist, Blocks Channel Activation by Vanilloids, Heat and Acid. J. Pharmacol. Exp. Ther. published 18 April 2005, 10.1124/jpet.105.084103

    Emerson & al., 1962. Resultats of the Puritan-AMNH Expedition to W.ern Mexico. 16. The Recent Mollusks: Gastropoda, Conidae. 44pp., 20figs. Hfl. 13.50

    Emerson 1968. A Record of the Indo-Pacific Cone, Conus ebraeus, in Guatemala. 1p. Hfl. 1.00

    Eichorn, A.(1916) - Die Herstellung von Muschelperlen aus Conus auf der Insel Ponam und ihre Verwendung im Kunsthandwerk der Admiralitaetsinsulaner. Baessler-Archiv, Vol. V, No. 6, 1916, pp. 256-283.

    Endean R, Gyr P, Surridge J.(1979)The effects of crude venoms of Conus magus and Conus striatus on the contractile response and electrical activity of guinea-pig cardiac musculature. Toxicon. 17(4):381-95.

    Endean R, Gyr P, Surridge J. (1977) The pharmacological actions on guinea-pig ileum of crude venoms from the marine gastropods Conus striatus and Conus magus. Toxicon. 15(4):327-37.

    Endean, R. and Rudkin, C. (1963) Studies on the venoms of some Conidae. Toxicon 1, 49 (1963)

    Endean, R. and Rudkin, C. (1965) Further studies of the venoms of Conidae. Toxicon. 69: 225-249. No abstract available.

    Endean R, Surridge J, Gyr P. (1977) Some effects of crude venom from the cones Conus striatus and Conus magus on isolated guinea-pig atria. Toxicon. 15(5):369-74.

    Endean R, Williams H, Gyr P, Surridge J. (1976) Some effects on muscle and nerve of crude venom from the gastropod Conus striatus. Toxicon. 14(4):267-74.

    Endean R, Parish G, Gyr P. (1974) Pharmacology of the venom of Conus geographus. Toxicon. 12(2):131-8.

    Endean R, Gyr P, Parish G. (1974) Pharmacology of the venom of the gastropod Conus magus. Toxicon. 12(2):117-29.

    Endean R, Duchemin C. (1967) The venom apparatus of Conus magus. Toxicon. 4(4):275-84.

    Fainzilber, M., Napchi, I., Gordon, D. and Zlotkin, E. (1994) Marine warning via peptide toxin. Scientific Correspondence, Nature (Lond.) 369: 192-193.
    [Abstract:[ C. striatus, C. textile, C. pennaceus, C. nussatella, C. arenatus, C. tesselatus, C. generalis, C. flavidus, C. rattus, C. parvatus, C. ventricosus, and Strombus. The results suggest the existence of phylogenetically specific alarm cues in Conidae. Only the molluscivorous species venoms were active against Strombus. This is the first documented case of a defined peptide acting as an interspecific alarm cue in marine ecosystems.]

    Fainzilber, M., Hasson, A., Oren, R., Burlingame, A.L., Gordon, D., Spira, M.E. and Zlotkin, E. (1994) New mollusc-specific alpha-conotoxins block Aplysia neuronal acetylcholine receptors. Biochemistry 33: 9523 - 9529.
    [Abstract:[ Conus pennaceus, alpha-CTX-PnIA/B, block neuronal nAChR in Aplysia, but not in brain of rat or fish]

    Fainzliber, M, Gordon, D, Hasson, A, Spira, M E, Zlotkin, E. (1991). Mollusc-specific toxins from the venom of Conus textile neovicarius. EUR J BIOCHEM 202 2 1991 EJBCA European Journal of Biochemistry 0014-2956 589-596.

    Fainzilber, M., Masson, A., Oren, R., Burlingame, A.L., Gordon, D., Spira, M.E. and Zlotkin, E. (1994) New mollusc specific a-conotoxins block Aplysia neuronal acetylcholine receptors. Biochemistry 33: 9523-9529.

    Fainzilber, M., Kofman, O., Zlotkin, E. and Gordon, D. (1994) The new neurotoxin site on sodium channels is identified by a conotoxin that affects sodium channel inactivation in molluscs and acts as an antagonist in the rat brain. J. Biol. Chem. 269: 2574-2580.
    [Abstract:[ Conus textile, delta-CTX-TxVIA, slows sodium current inactivation in mollusc neurons, protects toxic effects of textile venom in rat brain, 6 Cys/4 loop framework]

    Fainzilber, M., Nakamura, T., Gaathon, A., Lodder, J.C., Kits, K.S., Burlingame, A.L. and Zlotkin, E. (1995) A new cysteine framework in sodium channel blocking conotoxins. Biochemistry 34: 8649-8656.
    [Abstract:[ Conus pennaceus, mu-CTX-PnIVA/B, block sodium channels in molluscan neurons, no effect on sodium currents in bovine chromaffin cells or in rat brain synaptosomes]

    Cherry Farrow of The Guardian wrote on Conus, and its potential to provide a breakthrough in the fight against chronic pain.
    Small creature, big potential, The Guardian, Thursday February 12, 2004.
    For thousands of years, medical research has depended on plants, animals and microbes to understand and treat human disease. Now increasing attention is being paid to animals for sources of new medicines. One of the most unlikely and beautiful is a small, deadly mollusc - the cone snail.
    There is growing excitement among scientists that this marine snail may provide a breakthrough in the development of a series of new painkillers. Cone snails may contain more medicines than any other animal.
    A new synthetic drug, Prialt, is now at an advanced stage in clinical trials for the treatment of what is classed as intractable pain - unremitting, untreatable pain. Prialt, derived from the venom or conotoxin of the snail, may be 1,000 times stronger than morphine but without the tolerance or addiction usually associated with opiates.
    Cone snails live in shallow tropical waters, on reefs, in mangrove swamps and mud flats. There are thought to be approximately 500 species, although research has focused mainly on three. The snails have a little harpoon or fleshy foot from which they inject a lethal cocktail of toxins into their prey - other molluscs, worms and fish. They can "shake" the cocktail and create a new mix of changing proportions so their victims cannot develop immunity. Each species has evolved to produce its own set of toxins, about 100, which means there could be as many as 50,000 conotoxins in all.
    This is unprecedented in the biological world, says Aaron Bernstein, who is currently conducting research at Harvard Medical School.
    "It's the sheer diversity of the chemicals they make. The cone snail is young in evolutionary terms - only 50m years old - yet each has evolved a different number of toxins. Compare this to the 10,000 known alkaloids in plants, which we have been looking at for centuries," he said.
    Reseach into cone snails started 20 years ago. Experiments suggest that conotoxins could treat muscle spasticity, following spinal injury and epilepsy, that is resistant to traditional medicines. A broad spectrum anti-epileptic agent is currently in the first stage of clinical trials.
    For years, scientists have searched for a medicine that is very specific, effective at low doses and does not cause side effects of addiction or tolerance. Having to keep increasing doses to achieve the same results has always limited the long-term effectiveness of the opiates used for treating severe pain. Conotoxins do not behave like that -they are very potent in small concentrations, as trials carried out on patients with Aids and cancers have shown.
    "Most conotoxins are small peptides, 10 to 40 amino acids in length. They are exquisitely selective about their receptor binding sites," says Bernstein. "This makes them powerful tools for understanding how cells work, as well as a rich source for discovery of new medicines.What is remarkable about them is this ability to be so selective."
    Studies suggest that conotoxins could be used to treat muscle spasticity following spinal injuries and possibly prevent cell death during strokes or head injuries. They may also help in the treatment of small-cell lung cancer. By detecting the antibodies, contoxins can provide an early diagnostic test for some types of cancer.
    But it is in the treatment of "untreatable" pain that conotoxin research is furthest advanced. The first large-scale trials show just how effective the new painkiller in its synthetic form may prove to be. Trial results showed no evidence of tolerance or addictive behaviour and in feasibility studies with Aids and cancer patients with chronic pain there was relief in more than half of the patients.
    All this from a small marine snail that may, in the words of Eric Chivian, founder and director of the Centre for Human Health and Global Environment at Harvard Medical School, "contain the largest and most clinically important pharmacopoeia of any genus in nature." However, the reefs, mud and swamps in which they thrive are all under threat from over-fishing, pollution, mangrove clearance for coastal development, shrimp farming and "bioprospecting" - for private collections as well as the biomedical industry. Millions of cone snails are imported into the US and Europe every year.
    "We cannot find any country that monitors this trade," says Chivian. "Although a number of researchers are careful about moving quickly to synthesise the toxins they need, others may not be. No one knows how many and what species are being sacrificed for research and for the ornamental trade in their shells," he says. Global warming is also damaging their ocean habitat. "The loss of species deprives us of invaluable tools for biomedical research. They can give us the insight into health and illness," he adds. "So just as we are appeciating the remarkable potential of the cone snail, they are coming under intense pressure."

    Favreau, P., Gilles, N., Lamthanh, H., Bournaud, R., Shimahara, T., Bouet , F., Laboute, P., Letourneux, Y., Menez, A., Molgo, J. and Le Gall, F. (2001) A new omega-conotoxin that targets N-type voltage-sensitive calcium channels with unusual specificity. Biochemistry, 40: 14567-14576.
    Abstract: Research has been conducted on the voltage-sensitive calcium channel blocker isolated from the fish-hunting cone snail's venom. Results indicate that this peptide consists of amino acid residues folded by the disulfide bridges and represents a tool for blocking N-type voltage-sensitive calcium channels.

    Favreau, P., Krimm, I., Le Gall, F., Bobenrieth, M.J., Lamthanh, H., Bouet, F., Servent, D., Molgo, J., Menez, A., Letourneux, Y. and Lancelin, J-M. (1999) "Biochemical Characterization and Nuclear Magnetic Resonance Structure of Novel alpha-Conotoxins Isolated from the Venom of Conus consors". Biochemistry 38: 6317-6326.

    Abstract:
    [alpha-CnIA and alpha-CnIB are very similar in structure to alpha-conotoxin-MI (from C. magus). alpha-CnIA has a Tyr (Y) in position 11, instead of the Asn (N) in alpha-MI. alpha-CnIA and CnIB possess the three/five loop structure of conotoxins GI, GIA, GII,MI, SI, SIA, and SII (alpha3/5 subclass). These peptides were characterized by binding experiments with Torpedo nicotinic acetylcholine receptor (nAChR)and by NMR.  alpha-CnIA appears to be a potent and selective blocker of muscle-type nAChRs as evidenced by electrophysiological recordings with amphibian and mammalian isolated neuromuscular preparations].

    Fegan, D. and Andresen, D. (1997) Conus geographus envenomation. The Lancet. 349: 1672.

    Fiene-Severns, P., Severns, M. and Dyerly, R. (1998) Tropical Seashells of Thailand and South East Asia. (Cone Shells, Family Conidae, p. 44) ASIA Books, ISBN 962-593-175-9.

    Filmer R.M., (2001) A catalogue of nomenclature and taxonomy in the living Conidae 1758-1998; In 8vo, broch., pp. 387; LIT. 135000 (about USD 60.00)

    An important tool for cone collectors

    Fischer, H., Liu, D.M., Lee, A., Harries, J.C. and Adams, D.J. (2005) Selective modulation of neuronal nicotinic acetylcholine receptor channel subunits by Go-protein subunits. J Neurosci. 25:3571-3577.
    School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia.

    Abstract: G-protein modulation of neuronal nicotinic acetylcholine receptor (nAChR) channels in rat intrinsic cardiac ganglia was examined using dialyzed whole-cell and excised membrane patch-recording configurations. Cell dialysis with GTPgammaS increased the agonist affinity of nAChRs, resulting in a potentiation of nicotine-evoked whole-cell currents at low concentrations. ACh- and nicotine-evoked current amplitudes were increased approximately twofold in the presence of GTPgammaS. In inside-out membrane patches, the open probability (NP(o)) of nAChR-mediated unitary currents was reversibly increased fourfold after bath application of 0.2 mm GTPgammaS relative to control but was unchanged in the presence of GDPbetaS. The modulation of nAChR-mediated whole-cell currents was agonist specific; currents evoked by the cholinergic agonists ACh, nicotine, and 1,1-dimethyl-4-phenylpiperazinium iodide, but not cytisine or choline, were potentiated in the presence of GTPgammaS. The direct interaction between G-protein subunits and nAChRs was examined by bath application of either G(o)alpha or Gbetagamma subunits to inside-out membrane patches and in glutathione S-transferase pull-down and coimmunoprecipitation experiments. Bath application of 50 nm Gbetagamma increased the open probability of ACh-activated single-channel currents fivefold, whereas G(o)alpha (50 nm) produced no significant increase in NP(o). Neuronal nAChR subunits alpha3-alpha5 and beta2 exhibited a positive interaction with G(o)alpha and Gbetagamma, whereas beta4 and alpha7 failed to interact with either of the G-protein subunits. These results provide evidence for a direct interaction between nAChR and G-protein subunits, underlying the increased open probability of ACh-activated single-channel currents and potentiation of nAChR-mediated whole-cell currents in parasympathetic neurons of rat intrinsic cardiac ganglia.

    Flecker, H. (1936) Cone shell mollusc poisoning, with report of a fatal case. The Medical Journal of Australia, April 4, 1936, 464-466.
    [Abstract:[Conus geographus, Haymen Is., Great Barrier Reef, North Queensland, Indo-Pacific]

    Flinn JP, Pallaghy PK, Lew, M.J., Murphy, R., Angus, J.A., Norton, R.S. (1999) "Roles of key functional groups in omega-conotoxin GVIA Synthesis, structure and functional assay of selected peptide analogues". Eur J Biochem 262: 447-455.
    Abstract: The contributions of various functional groups to the pharmacophore of the N-type calcium-channel blocker, GVIA, were investigated using structural and in-vitro functional studies of analogues substituted at one or two positions with non-native residues. Three functional assays (sympathetic nerve stimulation of rat isolated vas deferens, right atrium and mesenteric artery) were employed to monitor N-type calcium-channel activity. The data provide a detailed picture of which residues are important for activity [see also alanine scan Lew et al. (1997) J. Biol. Chem. 272, 12014-12023 ]. A disubstituted chimera of GVIA and omega-conotoxin MVIIA was more potent than either native molecule. The more detailed description of the GVIA pharmacophore obtained here provides a better basis for the future design of truncated peptide and peptidomimetic analogues.

    Flores, C.M. and Mogil, J.S. (2001) The pharmacogenetics of analgesia: toward a genetically-based approach to pain management. Pharmacogenomics 2: 177-194.
    Abstract: Interindividual differences in the experience of pain have been appreciated clinically for over a century. More recently, there has been a growing body of evidence demonstrating differences in analgesic response to various pharmacotherapies, although the source of this variability largely remains to be explained. To this end, basic science research is beginning to identify the allelic variants that underlie such antinociceptive variability using a multiplicity of animal models, and powerful genetic approaches are being exploited to accelerate this process. Although the vast majority of these studies have focused on the pharmacogenetics of opioids, owing to their prominent status as analgesics, the number of pharmacotherapies evincing genetically-based variability is rapidly expanding. In addition, analogous studies have been undertaken in humans, as a small but growing number of clinical trials have begun to evaluate prospectively the existence, if oftentimes not the origin, of interindividual differences in analgesic drug response. Importantly, with a few notable exceptions, such efforts have primarily identified differences in analgesic efficacy and/or potency between male and female human subjects. Looking toward the future development of one or more widely utilised, pharmacogenetic screens that would lead to modifications in treatment planning, at least with respect to the pharmacologic management of pain, this review will document the breadth of genetically-based variability in drug-mediated antinociception in animals. Specific examples in which the gene or genes underlying such variability have been postulated or identified will be given, while highlighting the effect of sex and its interactions with other genetic backgrounds. Finally, we will summarise and evaluate the literature on pharmacogenetic differences in human analgesic drug response, for which the influence of sex has served as one of the better studied and heuristically insightful examples.

    Flores, C.M., Wilson, S.G. and Mogil, J.S. (1999) Pharmacogenetic variability in neuronal nicotinic receptor-mediated antinociception. Pharmacogenetics. 9: 619-625.
    Abstract: The ability to predict interindividual differences in drug efficacy or toxicity, based on genetic factors that influence drug disposition or drug action, is fast becoming a realistic goal. The purpose of the present study was to determine whether epibatidine, a prototypical nicotinic analgesic drug, exhibits pharmacogenetic variability in antinociceptive activity. Eight inbred mouse strains (A, AKR, BALB/c, C3H/He, C57BL/6, C57BL/10, DBA/2, and SM) were surveyed for their sensitivity to the antinociceptive effects of epibatidine. All strains exhibited statistically significant antinociception that peaked between 10 and 20 min following the systemic injection of 50 microg/kg epibatidine. However, there was fourfold variability in the magnitude of peak effect between strains, with DBA/2, BALB/c and A strains showing much greater sensitivity than all others. A return to baseline nociceptive threshold at 30 min post-injection was observed for all but the A strain. In contrast, these mice exhibited significant antinociception for at least 3 h following epibatidine administration. Thus, expressing the data as area under the time-latency curve to take into account both the magnitude and duration of effect, epibatidine displayed approximately 20-fold higher antinociceptive potency in the A strain compared with the C3H/He strain. The effects of epibatidine in both the A and C3H/He strains were dose-dependent and sensitive to antagonism by the selective neuronal nicotinic channel blocker mecamylamine. Taken together, these data demonstrate the existence of pharmacogenetic variability in neuronal nicotinic receptor-mediated antinociception between inbred stains of mice and presage the potential for similar variability in analgesic response to nicotinic-based analgesics among humans. Future studies will seek to identify the chromosomal loci underlying this variability.

    Franco, A. and Mari, F. (1999) "Three-dimensional structure of a-conotoxin EI determined by 1H NMR spectroscopy". Letters in Peptide Science 6: 199-207.
    Abstract: alpha-Conotoxin EI is an 18-residue peptide (RDOCCYHPTCNMSNPQIC;4–10, 5–18) isolated from the venom of Conus ermineus, the only fish-hunting cone snail of the Atlantic Ocean. This peptide targets specifically the nicotinic acetylcholine receptor (nAChR) found in mammalian skeletal muscle and the electric organ Torpedo, showing a novel selectivity profile when compared to other alpha-conotoxins. The 3D structure of EI has been determined by 2D-NMR methods in combination with dynamical simulated annealing protocols. A total of 133 NOE-derived distances were used to produce 13 structures with minimum energy that complied with the NOE restraints. The structure of EI is characterized by a helical loop between Thr^9 and Met^12 that is stabilized by the Cys^4-Cys^10 disulfide bond and turns involving Cys^4-Cys^5 and Asn^14-Pro^15. Other regions of the peptide appear to be flexible. The overall fold of EI is similar to that of other alpha 4/7-conotoxins (PnIA/B, MII, EpI). However, unlike these other alpha 4/7-conotoxins, EI targets the muscular type nAChR. The differences in selectivity can be attributed to differences in the surface charge distribution among these alpha 4/7-conotoxins. The implications for binding of EI to the muscular nAChR are discussed with respect to the current NMR structure of EI.

    Luis Gandía, Baldomero Lara , Julita S. Imperial , Mercedes Villarroya , Almudena Albillos , Rosario Maroto , A. G. García , Baldomero M. Olivera . (1997) Analogies and differences between w-conotoxins MVIIC and MVIID binding sites and functions in bovine chromaffin cells. Pflugers Archiv.- Europ J. Pharmacol. 435 55-64.
    Key words: Calcium channels, Q channels, Chromaffin cells, w-Conotoxin MVIIC, w-Conotoxin MVIID, 45Ca2+ uptake, Catecholamine release.

    [Conus magus, see JAMA November, 1995, William G. Brose, director of the Pain Clinic at Stanford university School of Medicine reported on SNX-111, a modified conotoxin with 100-1000 times analgesic potency of morphine and not addictive, useful against severe pain]

    Gatto GJ, Bohme GA, Caldwell WS, Letchworth SR, Traina VM, Obinu MC, Laville M, Reibaud M, Pradier L, Dunbar G, Bencherif M. (2004) TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects.CNS Drug Rev.10(2):147-166.
    Preclinical Research, Targacept, Inc. 200 East First Street, Suite 300, Winston-Salem, NC 27101-4165, USA.


    Abstract: The development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC-1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC-1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not develop following repeated administration of TC-1734. Its pharmacokinetic (PK) profile (half-life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC-1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demonstrated TC-1734's favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg. The bioavailability, pharmacological, pharmacokinetic, and safety profile of TC-1734 provides an example of a safe, potent and efficacious neuronal nicotinic modulator that holds promise for the management of the hallmark symptomatologies observed in dementia. Publication Types: Review Review, Tutorial

    Gibbs, W.W. (1996) A new way to spell relief: V-e-n-o-m, a toxin from killer sea snails promises a better painkiller. Scientific American 274: 20-21.
    [Abstract: The only thing worse than a pain- filled life is a painful death. Both are altogether too common. The World Health Organization estimates that on any given day over three million people struggle with chronic pain from cancer alone. In the U.S., a study published last November in the Journal of the American Medical Association revealed that of thousands of terminal patients interviewed at five major hospitals, about half spent their final days in agony. The study's authors laid much of the blame at the feet of a medical culture that chases miracles to the bitter end rather than doing its best to assuage suffering.

    But there is another reason that medicine so often fails to offer relief: doctors still have few weapons against pain, and each has major drawbacks. Aspirin and other over-the-counter remedies are far too weak for most chronic conditions. Narcotics such as morphine often work for a while, but many patients quickly become physically dependent and require ever stronger infusions. Eventually, says William G. Brose, director of the Pain Clinic at the Stanford University School of Medicine, "opiatetolerant patients feel no effect even from a dose thousands of times stronger than that needed to kill you or me." As a result, many sufferers can obtain comfort only at the cost of their faculties.

    Gonor, J.J. 1966. Escape responses of N. Borneo Strombid gastropods elicited by the predatory prosobranchs Aulica vespertilio & Conus marmoreus . Veliger 8 (4) 226-230.

    Gouda, H., Yamazaki, K-i., Hasegawa, J., Kobayashi, Y., Nishiuchi, Y., Sakakibara, S. and Hirono, S. (1997) Solution structure of alpha-conotoxin MI determined by (1)H-NMR spectroscopy and molecular dynamics simulation with the explicit solvent water. BBA - Proteins and Proteomics, 1343: 327-334.

    Goya P., Jagerovic N., Hernandez-Folgado L. and Martin M.I. (2003) Cannabinoids and Neuropathic Pain. Mini Reviews in Medicinal Chemistry 3: 765-772
    Abstract:This review presents available clinical studies and new insights into mechanisms of analgesic effect and possible new routes of administration of antidepressant drugs. Older TCAs continue to be superior treatments. We focused on recent findings on newer antidepressants as analgesics. Their use should be supported by further controlled trials. PMID: 14529518 [PubMed - in process]

    Gray, W.R., Luque, A., Olivera, B.M., Barrett, J. and Cruz, L.J. (1981) Peptide toxins from Conus geographus venom. J. Biol. Chem. 256: 4734-4740.
    [Abstract:[Conus geographus, Indo-Pacific, GI, GIA, GII]

    Gray, W.R., Rivier, J.E., Galyean, R., Cruz, L.J. and Olivera, B.M. (1983) Conotoxin MI. Disulfide bonding and conformational states. J. Biol. Chem. 258: 12247-12251.
    [Abstract:[Conotoxin MI and GI , selectivity in mice, MI/GI=2.5/1]

    Groebe, D.R., Dumm, J.M., Levitan, E.S., and Abramson, S.N. (1995) alpha-Conotoxins selectively inhibit one of the two acetylcholine binding sites of nicotinic receptors. Mol Pharmacol, 48: 105-111.
    [Conus magus, alpha-conotoxin MI, alpha 3/5 group, Indo-Pacific]
    Abstract
    Muscle subtypes of the nicotinic acetylcholine receptor contain two acetylcholine binding sites that can be distinguished pharmacologically. The affinities of several alpha-conotoxins for the two acetylcholine binding sites on nicotinic receptors from BC3H1 cells and Torpedo electric organ were investigated. alpha-Conotoxins MI, GI, and SIA each inhibited the binding of 125I-alpha-bungarotoxin to nicotinic acetylcholine receptors on BC3H1 cells with two distinct and independent affinities, which differed by 10,000-fold. The affinities of alpha-conotoxins SI and SII were significantly lower and the differences in the affinities of each of these toxins for the two sites were < 400-fold. alpha-Conotoxins MI, GI, SIA, and SI had higher affinity for the acetylcholine binding site near the alpha/delta subunit interface of nicotinic receptors from BC3H1 cells. However, when assessed using nicotinic receptors from Torpedo electric organ, alpha-conotoxin MI displayed higher affinity for the acetylcholine binding site near the alpha/gamma subunit interface. These observations suggest that species variations in the sequences of the gamma and delta subunits resulted in a dramatic reversal of the relative affinities of the alpha-conotoxins for each acetylcholine binding site. Some of the practical implications of these observations are discussed.

    HABE & al., 1970. Description of New Subgenus & Species of Latiaxis from the S. China Sea. 4pp., 3figs., in English & Japanese. Euro 0.65

    HABE & al., 1970. Descriptions of 2 N.Sp. of Cone Shell from the Philippines & Taiwan. 3pp., 1pl., in English & Japanese. Euro 0.70

    HABE, 1965. 2 New Cones from Japan. 4pp., 1pl., in Japanese & English. Euro 0.85

    HABE, 1965. Notes on the Ivory Shell Genus Babylonia. 10pp., 1pl. Euro 1.75

    Hamann, G., (1990). In search of Conus hamanni. Hawaiian Shell News, 38 (1): 1 & 5

    Hann, R.M., Pagan, O.R., Gregory, L.M., Jacome, T. and Eterovic, V.A (1997) The 9-arginine residue of a-conotoxin GI is responsible for its selective high affinity for the ag agonist site on the electric organ acetylcholine receptor. Biochemistry 36: 9051-9056.

    Abstract: The agonist-binding domains of the electric organ nicotinic acetylcholine receptor are located at the ad and ag subunit interfaces. a-Conotoxins GI (from Conus geographus) and MI (from Conus magus) are competitive antagonists of this receptor and, like d-tubocurarine, bind to the ag site with much higher affinity than ot the ad site. In the present study, a-conotoxin SIA (from Conus striatus) also displayed strong affinity for the ag site but no measurable affinity tfor the ad site, thus showing even greater site selectivity. In contrast, a-conotoxin SI does not distinguish between the two agonist sites, although its sequence differs from that of GI at only three postions: GI, ECCNPACGRHYSC; SI, ICCNPACGPKYSC. Analogues of SI and GI modified at these three postions were studied to identify the determinants of GI's ag selectivity. Substituting arginine for proline at position 9 produced peptides which displayed "GI-like" selectivity for the ag site. Conversely, substituting proline for arginine at position 9 resulted in "SI-like" nonselective inhibitors. An SI analogue having alanine in place of proline 9 did not distinguish between the two agonist sites and displayed about the same affinity as SI, indicating the importance of the arginyl cation. Interchanging the residues at position 1 or at position 10 influenced the affinity for the receptor but did no measurably change peptide selectivity. Therefore, of the three sequence differences in SI and GI, the variation at position 9, proline and arginine, respectively, is sufficident to account for GI's selective high-affinity binding to the ag site on the electric organ acetylcholine receptor.

    HANNA, 1963. W. American mollusks of the genus Conus-2. 91pp.,11col.pls., 4figs., a few underlinings in pencil.

    Hart, S.(1997) Cone snail toxins take off; potent neurotoxins stop fish in their tracks - and may provide new pain therapies. (includes related articles on pain treatments based on conotoxins and the relationship between marine animal toxins and sodium channels)BioScience, 47: 131-135..
    Abstract: Marine snails called purple cones emit potent neurotoxins through a hollow harpoon, causing instant paralysis in their prey. These same toxins show promise as chronic pain treatment, such as in cancer and AIDS. They target a calcium channel subtype in nerve cells that carry pain impulses.

    Hanna & Strong, West American Mollusks of the Genus Conus (76 p., 6 pls) and two smaller papers by Ingram on Cypraeidae; All bound together in cloth. Library stamps. All published in Proceedings of the California Academy of Sciences. MG03293 € 36,00

    Harvey, A.,(2002) Toxins 'R' Us: more pharmacological tools from nature's superstore.Trends Pharmacol Sci. 23:201-203.
    Abstract: Conus venoms from marine cone snails continue to provide novel bioactive components. Two new classes of conopeptide specifically block alpha(1)-adrenoceptors (rho-conopeptide) and noradrenaline transporters (chi-conopeptides). Both classes are small peptides with two disulfide bonds. Rho-conopeptide is structurally similar to alpha-conotoxins, which block nicotinic acetylcholine receptors, whereas the chi-conopeptides are unrelated to other conotoxins. Both types of conopeptides are non-competitive blockers. Because these peptides demonstrate greater selectivity than current drugs in clinical use, they could lead to the development of improved therapeutics.

    Harvey, S.C., McIntosh, J.M., Cartier, G.E., Maddox, F.N. and Luetje, C.W. (1997) Determinants of specificity for alpha-conotoxin MII on alpha3/beta2 neuronal nicotinic receptors. Molecular Pharmacology 51: 336-342.
    Abstract: Conus magus, alpha-conotoxin MII, 16aa peptide, blocks neuronal nAChRs composed of a3b2 subunits. Identified residues on the a and b subunits of neuronal nAChRs that determine sensitivity to a-CTX MII. Screened series of a and b subunit chimeras to identify critical sequence segments. Then used site-directed mutagenesis to identify individual residues important in determination of a-CTX MII sensitivity of the a3b2 subunit combination. Results: for a3 subunit, sequence segments 121-181 and 181-195 were the determinants of sensitivity and Lys185 and Ile 188 are the critical residues. For b2 subunit, segment 54-63 is important for sensitivity and Thr 59 is an important residue. The only mutation that had an effect on sensitivity was b2 T59K. These receptors were significantly (4-fold) less sensitive to MII. MII block was not affected by introducing a negative charge (Asp = D) at residue 59 of b2 (T59D). The b2 T59D mutation had no effect on a-CTX MII sensitivity; see also Cartier et al., 1997 below]

    Hashimoto, K., Uchida, S., Yoshida, H., Nishiuchi, Y., Sakakibara, S. and Yukari, K. (1985) Structure-activity relations of conotoxins at the neuromuscular junction. Eur. J. Pharmac. 118: 351-354.
    [Abstract: Conotoxin GI and MI, GI is 2.5 times more potent than MI, selectivity for neuromuscular system, neostigmine reverses]

    Hasson, A, Fainzilber, M, Gordon, D, Zlotkin, E, Spira, M E. (1993). Alteration of Sodium Currents by New Peptide Toxins from the Venom of A Molluscivorous Conus Snail. EUR J NEUROSCI 5 1 1993 EJONE European Journal of Neuroscience 0953-816X 56-64.

    R.E.W. Hatley. (2002) Marine mollusks and the skin. Dermatologic Therapy 15: 38-43.
    Abstract: Human contact with marine mollusks such as shellfish, marine snails, octopuses, and squids may result in human illness including dermatologic disorders. These range from minor traumatic injury of the skin to more serious systemic illnesses that include dermatologic manifestations. Notable among these are dermatologic manifestations of illness caused by toxins from ingested mollusks, stings of the cone snail, and envenomation by the bite of the blue-ringed octopus. Cone snail and blue-ringed octopus envenomations, although rare, can be deadly due to neuromuscular paralysis. Management of dermatologic illnesses caused by marine mollusks depends upon the nature of the exposure. Attention to local measures is usually sufficient for minor cuts and abrasions. Conversely, cone snail and blue-ringed octopus envenomations require immediate attention, possibly including cardiopulmonary resuscitation.

    Haubrich, C., Frielingsdorf, V., Herzig, S., Schroder, H., Schwarting, R., Sturm, V. and Voges, J. (2000) N-type calcium channel blockers - tools for modulation of cerebral functional units ?. Brain Res. 855: 225 - 234

    Hawdon GM, Winkel KD. (1997) Venomous marine creatures.Aust Fam Physician. 26: 1369-1374.
    Australian Venom Research Unit, Cabrini Private Hospital.
    BACKGROUND: Many venomous marine creatures inhabit Australian waters, causing significant morbidity and occasional fatalities. No antivenom is available for most of these creatures. Little is known about the venom or syndromes produced by many of these creatures. OBJECTIVE: This article discusses the features of envenomation by some of the more commonly encountered venomous marine creatures, and the recommended first aid and medical management of such envenomations. DISCUSSION: The information contained within this article is intended to provide the reader with an overview of some of the more common marine envenomations, and hopefully with the knowledge to effectively manage such problems.
    Comment in: Aust Fam Physician. 1998 May;27(5):343-4. Aust Fam Physician. 1998 May;27(5):344.

    Heading, C.E., 1999. Ziconotide, Neurex Corp. Current Opinion in CPNS Investigational Drugs 1, 153-166.

    Heading, C.E., 2001. Ziconotide (Elan Pharmaceuticals). IDrugs 4, 339-350.

    Heading, C.E., 2002. Conus peptides and neuroprotection. Curr Opin Investig Drugs 3, 915-920.

    Heiman, E.L.., ( 2002) Shells of East Sinai, an illustrated list. Conidae. Triton, 5: 19-23.

    Heiman, E.L., (2002) Shells of East Sinai an illustrated list. Conidae. Triton, Supplement 1: 1-10.

    Hill, J.M., Atkins, A.R., Loughnan, M.L., Jones, A., Adams, D.A., Martin, R.C., Lewis, R.J., Craik, D.J. and Alewood, P.F. (2000)Conotoxin TVIIA, a novel peptide from the venom of Conus tulipa: 1. Isolation, characterization and chemical synthesis. Europ. J. Biochem. 267: 4642-4649..
    Abstract: A novel conotoxin belonging to the `four-loop' structural class has been isolated from the venom of the piscivorous cone snail Conus tulipa. It was identified using a chemical-directed strategy based largely on mass spectrometric techniques. The new toxin, conotoxin TVIIA, consists of 30 amino-acid residues and contains three disulfide bonds. The amino-acid sequence was determined by Edman analysis as SCSGRDSRCOOVCCMGLMCSRGKCVSIYGE where O = 4-transl-hydroxyproline. Two under-hydroxylated analogues, Pro10TVIIA and Pro10,11TVIIA, were also identified in the venom of C. tulipa. The sequences of TVIIA and Pro10TVIIA were further verified by chemical synthesis and coelution studies with native material. Conotoxin TVIIA has a six cysteine four-loop structural framework common to many peptides from Conus venoms including the omega-, delta- and kappa-conotoxins. However, TVIIA displays little sequence homology with these well-characterized pharmacological classes of peptides, but displays striking sequence homology with conotoxin GS, a peptide from Conus geographus that blocks skeletal muscle sodium channels. These new toxins and GS share several biochemical features and represent a distinct subgroup of the four-loop conotoxins.

    Hill, J.M., Alewood, P.F. and Craik, D.J.(2000) Conotoxin TVIIA, a novel peptide from the venom of Conus tulipa : 2. Three-dimensional solution structure. Europ J Biochem. 267: 4649-4658. .
    Abstract: The three-dimensional solution structure of conotoxin TVIIA, a 30-residue polypeptide from the venom of the piscivorous cone snail Conus tulipa, has been determined using 2D 1H NMR spectroscopy.TVIIA contains six cysteine residues which form a `four-loop' structural framework common to many peptides from Conus venoms including the omega-, delta-, kappa-, and O-conotoxins. However, TVIIA does not belong to these well-characterized pharmacological classes of conotoxins, but displays high sequence identity with conotoxin GS, a muscle sodium channel blocker from Conus geographus. Structure calculations were based on 562 interproton distance restraints inferred from NOE data, together with 18 backbone and nine side-chain torsion angle restraints derived from spin-spin coupling constants. The final family of 20 structures had mean pairwise rms differences over residues 2-27 of 0.18 +- 0.05 A for the backbone atoms and 1.39 +- 0.33 A for all heavy atoms. The structure consists of a triple-stranded, antiparallel beta sheet with +2x, 1 topology (residues 7-9, 16-20 and 23-27) and several beta turns. The core of the molecule is formed by three disulfide bonds which form a cystine knot motif common to many toxic and inhibitory polypeptides. The global fold, molecular shape and distribution of amino-acid sidechains in TVIIA is similar to that previously reported for conotoxin GS, and comparison with other four-loop conotoxin structures provides further indication that TVIIA and GS represent a new and distinct subgroup of this structural family. The structure of TVIIA determined in this study provides the basis for determining a structure-activity relationship for these molecules and their interaction with target receptors.

    Hill, J.M., Oomen, C.J., Miranda, L.P., Bingham, J.-P., Alewood, P.F. and Craik, D.J. (1998) Three-Dimensional Solution Structure of a-Conotoxin MII by NMR Spectroscopy: Effects of Solution Environment on Helicity. Biochemistry 37 15621-15630.

    Hinegardner, R.T. (1958) The venom apparatus of the cone shell. Hawaii Medical Journal 17: 533-563.

    Hogg, R.C. and Bertrand, D. (2004) Nicotinic acetylcholine receptors as drug targets. Curr Drug Targets CNS Neurol Disord. 3:123-130.
    Department of Physiology, CMU, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland. hogg1@etu.unige.ch

    Abstract: While it has long been documented that nicotine contained in tobacco leaves gives rise to major public health problems it has also been observed that this alkaloid can have beneficial effects. However, it is only with the identification of a family of genes coding for the neuronal nicotinic acetylcholine receptors and increased knowledge of their expression and function in the central nervous system that these receptors have received attention concerning their potential as drug targets. In light of the latest findings about nicotinic acetylcholine receptors and their involvement in disease states we review the possibility to design new drugs targeted to these ligand-gated channels. Beneficial and possible undesirable actions of agonists, antagonists and allosteric modulators are discussed and placed in perspective of our most recent knowledge.

    Hopkins, C., Grilley, M., Miller, C., Shon, K.-J., Cruz, L.J., Gray, W.R., Dykert, J., Rivier, J., Yoshikami, D. and Olivera, B.M. (1995) A new family of Conus peptides targeted to the nicotinic acetylcholine receptor. J. Biol. Chem. 270: 22361-22367.
    [Conus purpurascens, the purple cone, alphaA-conotoxin PIVA, Gulf of California - eastern Pacific]
    Abstract
    In this work, a new family of Conus peptides, the alpha A-conotoxins, which target the nicotinic acetylcholine receptor, is defined. The first members of this family have been characterized from the eastern Pacific species, Conus purpurascens (the purple cone)., three peptides that cause paralysis in fish were purified and characterized from milked venom. The sequence and disulfide bonding pattern of one of these, alpha A-conotoxin PIVA, is as follows: [formula: see text] where O represents trans-4-hydroxyproline. The two other peptides purified from C. purpurascens venom are the under-hydroxylated derivatives, [Pro13]alpha A-conotoxin PIVA and [Pro7,13]alpha A-conotoxin PIVA. The peptides have been chemically synthesized in a biologically active form. Both electrophysiological experiments and competition binding with alpha-bungarotoxin demonstrate that alpha A-PIVA acts as an antagonist of the nicotinic acetylcholine receptor at the postsynaptic membrane.

    Hori, S., Okutani, T. (1996). A New Pyramidellid Gastropod Ectoparasitic on Conus. Venus, Japanese J. Malacology 55(1):7-14. {Coneodostomia okamurai, Boonea okamurai n.spp., RhizoConus, VirroConus}

    HÖRNES & al., 1851. Die fossilen Mollusken Des Tertiaer-Beckens von Wien. - No 1. Conus. 42pp., 5pls.,

    Hovda, D.A., Fu, K., Badie, H., Samii, A., Pinanong, P. and Becker, D.P. (1994) Administration of an omega-conopeptide one hour following traumatic brain injury reduces 45calcium accumulation. Acta Neurochir Suppl (Wien) 60: 521-523. [SNX-111, NIH 95067173]

    Huang, C.-C., Lyu, P.-C., Lin, C.-H. and Hsu, K.-S. (1997) Conantokin-T selectively antagonizes N-methyl-d-aspartate-evoked responses in rat hippocampal slice.Toxicon, 35: 355-364. .
    Abstract: This study investigated the mode of action of conantokin-T, a 21 amino acid peptide toxin isolated from the venom of the fish-hunting cone snail Conus tulipa, on excitatory synaptic transmission in rat hippocampal slices using intracellular recording techniques. Superfusion of conantokin-T (1-500 nM) specifically and irreversibly decreased the pharmacologically isolated N-methyl-d-aspartate receptor (NMDA)-mediated excitatory postsynaptic potential (EPSPNMDA) in a concentration-dependent manner but had no effect on normal excitatory synaptic transmission (EPSP). The sensitivity of postsynaptic neurons to NMDA but not to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid was also antagonized by conantokin-T pretreatment. In addition, the conantokin-T-induced depression of EPSPNMDA could be antagonized by prior treatment of hippocampal slices with eitherdl-2-amino-5-phosphonovaleate (10 muM) or ifenprodil (20 muM). However, 7-chlorokynurenic acid (1 muM) had no effect on the action of conantokin-T. These findings indicated that conantokin-T modulates the NMDA receptor by an interaction with its glutamate binding site and polyamine recognition site.

    Humblet, C., Narasimhan, L. and Singh, J. (1995)Snail and spider toxins share similar tertiary structure and 'cystine motif'Toxicon, 33: 270. .
    Abstract: The multi-disulphide bridged peptide toxins, omega-conotoxin GVIA from the venom of the cone snail, Conus geographus, and omega-agatoxins IVA and IVB from the venom of the funnel-web spider Agelenopsis aperta, have become-valuable tools for studying the physiology, pharmacology and anatomical distribution of neuronal voltage-sensitive calcium channels. A comparison of the structures of omega-conotoxin GVIA and omega-agatoxin IVB will be presented with particular focus on the structural role of their disulphides. Despite the difference in size, these toxins have a similar location and disulphide connectivity of half-cystines. The tertiary structures of the two toxins show remarkable similarity. Both toxins fold into a triple-stranded beta-sheet with a +2x, - 1 topology. A sequence alignment indicates a 27% sequence identity, most of which (23%) is accounted for by the half-cystines. The low level of identity between residues other than half-cystines suggests that the structural similarity observed is prominently dictated by the relationship between their cystine motifs. Toxins from snail venoms have been shown to present a common cystine pattern despite very low primary sequence homology. Interestingly, the example presented here shows that similar cystine motifs are found in toxins that originate from different animal species. The structural similarity, in relation to the similar cystine motifs, might imply a common tertiary structure for toxins that share this core. On that basis, the present observation provides a rationale for model-building of toxins which possess a similar cystine motif.

    Ibanez-Tallon I, Wen H, Miwa JM, Xing J, Tekinay AB, Ono F, Brehm P, Heintz N. (2004) Tethering naturally occurring Peptide toxins for cell-autonomous modulation of ion channels and receptors in vivo. Neuron. 43:305-311.
    Howard Hughes Medical Institute, Laboratory of Molecular Biology, The Rockefeller University, New York, NY 10021 USA.
    Abstract: The physiologies of cells depend on electrochemical signals carried by ion channels and receptors. Venomous animals produce an enormous variety of peptide toxins with high affinity for specific ion channels and receptors. The mammalian prototoxin lynx1 shares with alpha-bungarotoxin the ability to bind and modulate nicotinic receptors (nAChRs); however, lynx1 is tethered to the membrane via a GPI anchor. We show here that several classes of neurotoxins, including bungarotoxins and cobratoxins, retain their selective antagonistic properties when tethered to the membrane. Targeted elimination of nAChR function in zebrafish can be achieved with tethered alpha-bungarotoxin, silencing synaptic transmission without perturbing synapse formation. These studies harness the pharmacological properties of peptide toxins for use in genetic experiments. When combined with specific methods of cell and temporal expression, the extension of this approach to hundreds of naturally occurring peptide toxins opens a new landscape for cell-autonomous regulation of cellular physiology in vivo.

    Jaret, P.(2003) Healing power of poison: yesterday's deadly venoms are today's strong medicines. Reader's Digest 162: 185..
    Abstract: Medical researchers are turning to some of nature's deadliest poisons as a way to heal people. A form of arsenic is being used to treat people with acute promyeolocytic leukemia. Venom from a cone snail can act as a natural painkiller that does not cause paralysis. Clostridium botulinum, the toxin which causes botulism, can be used to ease muscle spasms associated with cerebral palsy. Jarrett, A. and Slimming, D.. The cone shells of the Seychelles. Price: US$ 116.28 Go to www.abebooks.com to check it out.

    Jain, K.K. (2000) An evaluation of intrathecal ziconotide for the treatment of chronic pain. Expert Opinion on Investigational Drugs, 9: 2403-2411. .
    Abstract: Ziconotide, the synthetic form of cone snail peptide pi-conotoxin MVIIA, is a neurone-specific N-type calcium channel blocker with an analgesic and neuroprotective effect. Intrathecal ziconotide has been recommended for approval by the FDA for the management of chronic pain. Spinally administered ziconotide produces analgesia by blocking neurotransmitter release from primary nociceptive afferents and prevents the propagation of pain signals to the brain. It has an advantage over intrathecal morphine in that there is no development of tolerance after prolonged use. Systemic toxicity is considerably reduced by administration of smaller doses intrathecally and selective delivery to the site of action in the nervous system. Nevertheless, there are neurological adverse effects due to delay in clearance of ziconotide from the neural tissues. Overall, ziconotide has a favourable risk/benefit ratio with advantages over several currently available intrathecal therapies for pain.
    (Examples are given with tethered alpha- and kappa-bungarotoxin, alpha-conotoxin PnIB, alpha-conotoxin MII, uO-conotoxin MrVIA and omega-conotoxin MVIIA)

    Jimenez, E.C., Watkins, M., Juszczak, L.J. Cruz, L.J. and Olivera, B.M.(2001) Contryphans from Conus textile venom ducts. Toxicon, 39: 803-809.
    Abstract: Contryphans are unusual Conus peptides which contain a distinctive post-translational modification, d-tryptophan or d-leucine. cDNA clones encoding new contryphans from the mollusc-hunting cone snail Conus textile were identified and the inferred mature peptides were synthesized: contryphan-Tx (Gly-Cys-Hyp-d-Trp-Gln-Pro-Tyr-Cys-NH2), Leu-contryphan-Tx (Cys-Val-d-Leu-Tyr-Pro-Trp-Cys-NH2) and contryphan R/Tx which is identical to contryphan-R [Jimenez et al., 1996. Contryphan is a d-tryptophan containing Conus peptide. J. Biol. Chem. 281, 28002-28005]. Leu-contryphan-Tx exhibits a single peak, but contryphan-Tx shows two peaks under reverse-phase high-performance liquid chromatography conditions. Ultraviolet resonance Raman spectroscopy demonstrates a difference in the d-tryptophan dihedral angle for the two contryphan-Tx equilibrium conformers. Both the sequences and in vivo effects of all contryphans isolated suggest that there are two major branches of the contryphan family.

    Jimenez EC, Shetty RP, Lirazan M, Rivier J, Walker C, Abogadie FC, Yoshikami D, Cruz LJ, Olivera BM (2003). A new class of Conus peptides, the I-superfamily of conotoxins, has been characterized using biochemical, electrophysiological and molecular genetic methods. J Neurochem. 85: 610-21.
    Abstract: Novel excitatory Conus peptides define a new conotoxin superfamily. Peptides in this superfamily have a novel pattern of eight Cys residues. Five peptides that elicited excitatory symptomatology, r11a, r11b, r11c, r11d and r11e, were purified from Conus radiatus venom; four were tested on amphibian peripheral axons and shown to elicit repetitive action potentials, consistent with being members of the 'lightning-strike cabal' of toxins that effect instant immobilization of fish prey. A parallel analysis of Conus cDNA clones revealed a new class of conotoxin genes that was particularly enriched (with 18 identified paralogues) in a Conus radiatus venom duct library; several C. radiatus clones encoded the excitatory peptides directly characterized from venom. The remarkable diversity of related I-superfamily peptides within a single Conus species is unprecedented. When combined with the excitatory effects observed on peripheral circuitry, this unexpected diversity suggests a corresponding molecular complexity of the targeted signaling components in peripheral axons; the I-conotoxin superfamily should provide a rich lode of pharmacological tools for dissecting and understanding these. Thus, the I-superfamily conotoxins promise to provide a significant new technology platform for dissecting the molecular components of axons.

    Johnson, D.S., Martinez, J., Elgoyhen, A.B., Heinemann, S.S., and Macintosh, J.M. (1995) alpha-Conotoxin ImI exhibits sub-type specific nicotinic acetylcholine receptor blockade: Preferential inhibition of homomeric alpha7 and alpha9 receptors. Mol. Pharmacol. 48: 194-199.
    [Conus magus, Conus geographus, Conus imperialis , alpha-conotoxin MI,GI and ImI, MI and GI are alpha 3/5 group, ImI is alpha 4/3 group, MI and GI are fish-hunting, whereas ImI is non-fish hunting, all Indo-Pacific; In vivo ImI potent inhibitor of muscle nAChR in frog, but has no effect after i.p. injection into mice. ICV injections of ImI into mice or rats produce complex seizures suggesting selective targeting of neuronal-type mammalian AChRs ]
    Abstract
    Through a study of cloned nicotinic receptors expressed in Xenopus oocytes, we provide evidence that alpha-conotoxin ImI, a peptide marine snail toxin that induces seizures in rodents, selectively blocks subtypes of nicotinic acetylcholine receptors. alpha-Conotoxin ImI blocks homomeric alpha 7 nicotinic receptors with the highest apparent affinity and homomeric alpha 9 receptors with 8-fold lower affinity. This toxin has no effect on receptors composed of alpha 2 beta 2, alpha 3 beta 2, alpha 4 beta 2, alpha 2 beta 4, alpha 3 beta 4, or alpha 4 beta 4 subunit combinations. In contrast to alpha-bungarotoxin, which has high affinity for alpha 7, alpha 9, and alpha 1 beta 1 gamma delta receptors, alpha-conotoxin ImI has low affinity for the muscle nAChR. Related Conus peptides, alpha-conotoxins MI and GI, exhibit a distinct specificity, strictly targeting the muscle subtype receptor but not alpha 7 or alpha 9 receptors. alpha-Conotoxins thus represent selective tools for the study of neuronal nicotinic acetylcholine receptors.

    Jones, A., Bingham, J-P., Gehrmann, J., Bond, T., Loughnan, M., Atkins, A., Lewis, R.L. and Alewood, P.F. (1996) Isolation and characterisation of conopeptides by HPLC/MS and MS/MS. Rapid Commun. In Mass Spectrometry 10: 138-143.

    Jones, R.M. and Bulaj, G. (2000)Conotoxins: New vistas for peptide therapeutics. Curr. Pharmaceut. Design 6: 1249-1285.Full article available.

    KAICHER, S.D., 1977. Kaicher Cards. Card Catalogue of World-Wide Shells. Pack 13. Conidae; 106 cards. Only 60 packs of cards were issued between 1973 and 1992 and many of those are no longer available. Each card (12.5 x 8 cm) briefly describes one species and gives a figure or photograph of it (numerous type specimens were depicted). These cards have proved a useful tool for identification and have been praised by both amateur and professional malacologists.

    Karlin, A. (2002) Emerging Structure of the Nicotinic Acetylcholine Receptors Nature Reviews Neuroscience 3, 102-114.
    Preface The conversion of acetylcholine binding into ion conduction across the membrane is becoming more clearly understood in terms of the structure of the receptor and its transitions. A high-resolution structure of a protein that is homologous to the extracellular domain of the receptor has revealed the binding sites and subunit interfaces in great detail. Although the structures of the membrane and cytoplasmic domains are less well determined, the channel lining and the determinants of selectivity have been mapped. The location and structure of the gates, and the coupling between binding sites and gates, remain to be established.

    Summary

    • Nicotinic acetylcholine (ACh) receptors and other Cys-loop receptors challenge our ability to understand how proteins carry out simple sets of functions — in this case, specific binding, conversion of binding into channel opening, selective conduction, and desensitization.
    • The crystal structure of an ACh-binding protein that is homologous to the extracellular domain of the receptors has provided a detailed framework for interpreting the results of decades of biochemical work. The ACh-binding sites have been definitively located between subunits, with adjacent subunits contributing crucial residues.
    • A crystal structure of alpha-bungarotoxin bound to a synthetic peptide that mimics a binding-site loop of the ACh-binding protein has revealed the mode of binding of snake alpha-neurotoxins to the ACh receptors.
    • The structure of the channel lining, which is formed by the membrane-spanning segments of each of the five receptor subunits, has been inferred from photolabelling, mutagenesis, a combination of mutagenesis and chemical probing, and electron microscopy.
    • All of these approaches have provided evidence that extensive conformational changes accompany shifts of the receptor from one functional state to another.
    • Key among the changes are the opening and closing of gates, which are detected most sensitively by electrophysiological means. Inferences that have been made about the nature and location of these gates are not all in agreement.
    • The residues that determine the selectivity of the channel for the charge and size of permeating ions have been identified, but understanding the physical basis of their roles is likely to require a high-resolution structure of the protein.

    Igor Kasheverov, Anna Rozhkova, Maxim Zhmak, Yuri Utkin, Vadim Ivanov, and Victor I Tsetlin (2001) Photoactivatable alpha-conotoxins reveal contacts with all subunits as well as antagonist-induced rearrangements in the Torpedo californica acetylcholine receptor. Eur. J. Biochem. 268: 3664-3673

    Kauferstein, S., Huys, I., Lamthanh, H., Stocklin, R., Sotto F., Menez, A., Tytgat, J. and Mebs, D. (2003) A novel conotoxin inhibiting vertebrate voltage-sensitive potassium channels.Toxicon 42: 43-53..
    Abstract: Toxins from cone snail (Conus species) venoms are multiple disulfide bonded peptides. Based on their pharmacological target (ion channels, receptors) and their disulfide pattern, they have been classified into several toxin families and superfamilies. Here, we report a new conotoxin, which is the first member of a structurally new superfamily of Conus peptides and the first conotoxin affecting vertebrate K+ channels. The new toxin, designated conotoxin ViTx, has been isolated from the venom of Conus virgo and comprises a single chain of 35 amino acids cross-linked by four disulfide bridges. Its amino acid sequence (SRCFPPGIYCTSYLPCCWGICCSTCRNVCHLRIGK) was partially determined by Edman degradation and deduced from the nucleotide sequence of the toxin cDNA. Nucleic acid sequencing also revealed a prepropeptide comprising 67 amino acid residues and demonstrated a posttranslational modification of the protein by releasing a six-residue peptide from the C-terminal. Voltage clamp studies on various ion channels indicated that the toxin inhibits the vertebrate K+ channels Kv1.1 and Kv1.3 but not Kv1.2. The chemically synthesized product exhibited the same physiological activity and identical molecular mass (3933.7Da) as the native toxin.

    Kennedy C, Assis TS, Currie AJ, Rowan EG. (2003) Crossing the pain barrier: P2 receptors as targets for novel analgesics. J Physiol. 553 : 683-694.
    In 1995 the P2X3 receptor was found to be expressed at high levels in nociceptive sensory neurones, consistent with earlier reports that ATP induced pain in humans and animals. At first it was thought that ATP was most likely to play a role in acute pain, following its release from damaged or stressed cells and since then a wide variety of experimental techniques and approaches have been used to study this possibility. Whilst it is clear that exogenous and endogenous ATP can indeed acutely stimulate sensory neurones, more recent reports using gene knockout and antisense oligonucleotide technologies, and a novel, selective P2X3 antagonist, A-317491, all indicate that ATP and P2X3 receptors are more likely to be involved in chronic pain conditions, particularly chronic inflammatory and neuropathic pain. These reports indicate that P2X3 receptors on sensory nerves may be tonically activated by ATP released from nearby damaged or stressed cells, or perhaps from the sensory nerves themselves. This signal, when transmitted to the CNS, will be perceived consciously as chronic pain. In addition, it is now clear that several subtypes of P2Y receptor are also expressed in sensory neurones. Although their distribution and functions have not been as widely studied as P2X receptors, the effects that they mediate indicate that they might also be considered as therapeutic targets in the treatment of pain. Although our ability to treat persistent painful conditions, such as chronic inflammatory and neuropathic pain, has improved in recent years, these conditions are often resistant to currently available therapies, such as opioids or non-steroidal anti-inflammatory drugs. This reflects a limited understanding of the underlying pathophysiology. It is now clear that the development and maintenance of chronic pain are mediated by multiple factors, but many of these factors, and the receptors and mechanisms through which they act, remain to be identified. Chronic pain is debilitating and can greatly decrease quality of life, not just due to the pain per se, but also because of the depression that can often ensue. Thus a greater understanding of the mechanisms that underlie chronic pain will help identify new targets for novel analgesics, which will be of great therapeutic benefit to many people.

    KILBURN, R.N., 1971-1991. Collection of 12 papers on South African Gastropods; disbound (no covers). Published in: Annals Natal Museum. Including: A Revision of the Naticidae (56 p., 28 figs) / A Revision of the Littoral Conidae (18 p., 7 figs) / Taxonomic Studies on the Marine Mollusca of South Africa and Mozambique 1-2 (42, 8 p., 42, 13 figs). Available from Hermann Strack (Email: h.l.strack@planet.nl) www.strackbooks.nl

    Kilburn, R.N., (1972). Taxonomic notes on South African marine Mollusca (2), with the description of new species and subspecies of Conus, Nassarius, Vexillum and Demoulia. Ann. Natal Mus., 21 (2): 391-437

    Kilburn, R.N. (1998) Description of 4 new neogastropods of superfamilies Muricoidea and Conoidea from South Africa. 6pp. 9 figs.

    Kilburn, R.N. (1998). Description of 4 new neogastropods of superfamilies Muricoidea & Conoidea from S. Africa. 6pp., 9figs.

    Kim, J.I,, Takahashi, M., Ohtake, A., Wakamiya, A. and Sato, K. (1995) Tyr13 is essential for the activity of omega-conotoxin MVIIA and GVIA, specific N-type calcium channel blockers. Biochem Biophys Res Commun 206: 449-454.
    [Abstract:[SNX-111, NIH 95126938]

    Kits, K.S., Lodder, J.C., Van Der Schors, R.C., Li, K.W., Geraerts, W.P.M. and Fainzilber, M. (1996). Novel omega-conotoxins block dihydropyridine-insensitive high voltage-activated calcium channels in molluscan neurons. Journal of Neurochemistry 67: 2155-2163.

    Klein, R. C., Galdzicki, Z. and Castellino, F. J. (1999) Inhibition of NMDA-Induced Currents by Conantokin-T and Conantokin-G in Cultured Embryonic Murine Hippocampal Neurons. Neuropharmacology, 38, 1819-1829

    Kohn, A.J. et al Catalogue of Recent and fossil Conus, 1937 - 1995. [on-line at URL http://www.biology.washington.edu/akohn/]

    Kohn, A.J. (1958) Cone shell stings. Hawaii Medical Journal 17: 528-532.

    KOHN, A.J., 1963-1976. Type specimens and identity of the described species of Conus. The species described by Linnaeus, 1758-1767. II. The species described by Solander, Chemnitz, Born, and Lightfoot between 1766-1786. III. The species described by Gmelin and Blumenbach in 1791. IV. The species described by Hwass, Bruguičre and Olivi in 1792;. V. The species described by Salis Marschlins and Röding, 1793-1798. Chronological analysis of the species of Conus described in the 18th century; 6 parts bound in one. 230 p., 22 pls, black hcalf (spine gilt). Published in: Journal of the Linnean Society of London. Ex libris of Luis Pisani Burnay. A thorough study of the Conus species described in the 18th century, and beautifully bound. (Available from Hermann Strack (Email: h.l.strack@planet.nl) www.strackbooks.nl)

    Kohn, A.J.<1963>: Venomous marine snails of the genus Conus. In: Venomous and poisonous animals and noxious plants in the Pacific region (H.C. Keegan, M.V. McFarlane, Herausgeber), S. 83, Pergamon Press, Oxford (1963)

    KOHN, 1964. Mollusks [on a symposium on the Mollusca at the Zoological Society of London, 4-5 March 1964]. 2pp.

    Kohn AJ, Waters V. (1966) Escape responses to three herbivorous gastropods to the predatory gastropod Conus textile. Anim Behav. 14 (2):340-345.

    KOHN, 1966. Food specialization in Conus in Hawaii & California. 3pp., 1tab., 1fig. OLD, 1965. On the identity of Conus pastinaca. 4pp., 1pl.

    KOHN & al., 1972. Radula Tooth Structure of the Gastropod Conus imperialis Elucidated by Scanning Electron Microscopy. 3pp., 1fig., left bottom corner defective

    KOHN, 1975. Type specimens & identity of the described species of Conus 5. The species described by Salis Marschlins & Röding, 1793-8. 43pp., 1fig., 3pls., 2 Tables.

    .

    KOHN, 1976. Chronological analysis of the species of Conus described during the 18th century. 21pp., 1pl., 1fig., 1 Table.

    Kohn, A. J. (1980) Conus kahiko, a new Pleistocene gastropod from Oahu, Hawaii, Journal of Paleontology 54, 534-541.

    KOHN, 1986. Type specimens & identity of the described species of Conus 7. The species described 1810-20. 41pp., 34figs., 4 Tables.

    KOHN, 1988. Type specimens & identity of the described species of Conus. 8. The species described 1821-30. 52pp., 2 Tables., 39figs.

    Kohn, A.J. (1990) Tempo and mode of evolution of Conidae. Malacologia, 32: 55-67

    Kohn, A.J. & Amalsi, K.N. 1993. Comparative ecology of a biogeographically heterogeneous Conus assemblage. Pp. 523-538. In: Wells, F.E., Walker, D.I., Kirkman, H. and Lethbridge, R. (eds). The marine flora and fauna of Rottnest Island, Western Australia. Western Australian Museum, Perth

    Kohn, A.J., Nishi, M. and Pernet, B.(1999) Snail spears and scimitars: A character analysis of Conus radular teeth. J. Moll Stud 65: 461-481
    [Abstract: Conus sp. ...We define and provide a scheme for coding the states of Conus radualr tooth characters, in order to facilitate their use in taxonomic and phylogenetic studies........]

    Kohn, A.J.(2001)The feeding process in molluscivorous Conus. Proceedings World Congress of Malacology, Vienna, 19-25 August, 2001.
    Department of Zoology, University of Washington, Box 351800, Seattle, Washington 98195, USA.
    Abstract: In the gastropod genus Conus, each radular tooth functions independently as a critical component of the delivery system for conotoxins, neurotoxic venoms that are injected into prey organisms and paralyze them prior to ingestion. The morphology of Conus radular teeth varies among species according to their specialization on a major prey type, primarily polychaete annelids, fishes, or other gastropods. The few prior studies describing details of the feeding process focused on species that prey on polychaetes and fishes, in which the radular tooth functions like a hollow harpoon. When injected, it catches and holds the prey while venom is pumped through its lumen by muscular action of the proboscis, the prey is paralyzed and pulled into the rhynchodaeum by contraction of longitudinal proboscis muscles, and swallowed whole. The tooth passes through the Conus alimentary tract with the prey. The observation that the guts of molluscivorous species of Conus sometimes contain several of their own teeth as well as prey remains suggested that the feeding process differs from that of vermivores and piscivores, particularly that more than one tooth is injected into a single prey organism. Here I describe the behaviorally much more complex feeding process in a molluscivorous species for the first time. As predicted, it involves sequential injection of several teeth, each of which is released into the prey and is thus more analogous to an arrow from a bow than to a harpoon. A video illustrates details of the process and the responses of the gastropod prey to multiple envenomations.

    Kohn, AJ and Hunter, C (2001) The feeding process in Conus imperialis. The Veliger 44 (2) 232-235.

    KOHN, A. 2002. Comparative biology of Conus in the light of phylogeny: a preliminary report. 6pp., 1tab., 5figs., Italian summ. .

    Kohn, AJ (2003) The feeding process in Conus victoriae. in F.E. Wells, D.I. Walker and D.S. Jones (eds) 2003. The Marine Flora and Fauna of Dampier, Western Australia. Western Australian Museum, Perth. pp,. 101-107.

    Kohno, T., Kim, J.-I., Kobayashi, K., Kodera, Y., Maeda, T. and Sato, K. (1995) Three-dimensional structure in solution of the calcium channel blocker omega-conotoxin MVIIA. Biochemistry 34: 10256-
    [Abstract: Conus magus. Omega-conotoxin MVIIA = SNX-111. Refinement was via a distance geometry/simulated annealing protocol using NMR-derived restraints and X-PLOR 3.1. RMSD backbone heavy atoms 0.47 +/- 0.08; All heavy atoms 1.27 +/- 0.14 (See also Table 1 of the paper cited on journal records above).Brookhaven Data Bank accession 1OMG ]

    Kong L, Lee BT, Tong JC, Tan TW, Ranganathan S. (2004) W356-9. SDPMOD: an automated comparative modeling server for small disulfide-bonded proteins. Nucleic Acids Res. Jul 1;32(Web Server issue): W356-359, Also: Full free-text article on PubMedCentral
    Department of Biochemistry, National University of Singapore, 8 Medical Drive, 117597, Singapore.
    Abstract: Small disulfide-bonded proteins (SDPs) are rich sources for therapeutic drugs. Designing drugs from these proteins requires three-dimensional structural information, which is only available for a subset of these proteins. SDPMOD addresses this deficit in structural information by providing a freely available automated comparative modeling service to the research community. For expert users, SDPMOD offers a manual mode that permits the selection of a desired template as well as a semi-automated mode that allows users to select the template from a suggested list. Besides the selection of templates, expert users can edit the target-template alignment, thus allowing further customization of the modeling process. Furthermore, the web service provides model stereochemical quality evaluation using PROCHECK. SDPMOD is freely accessible to academic users via the web interface at http://proline.bic.nus.edu.sg/sdpmod.

    Application to conotoxin PnIA.
    (Extract from the Introduction to this paper)
    Small disulfide-bonded proteins (SDPs) are a special class of proteins that are relatively small in size (length < or = 100 residues) and have disulfide bonds within their three-dimensional (3D) structures (1). SDPs include many secretory proteins which serve predatory, defensive or regulatory roles (such as toxins, inhibitors and hormones), and they are rich source for therapeutic drugs (2) and pesticides (3). The 3D structures of SDPs are essential for understanding the functions of SDPs and for drug design. However, 3D structure determination through experimental methods such as X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy are still both time-consuming and expensive. This results in a gap between the number of known 3D structures and the number of primary sequences that could be narrowed using large-scale automated protein structure prediction.

    Among current structure prediction methods, comparative modeling is the most reliable method for generating 3D models. Comparative modeling of protein structures often requires expert knowledge and proficiency in specialized methods. In the mid-1990s, Peitsch and coworkers developed the first automated modeling server SWISS-MODEL (4), which is currently the most widely used server of this genre. Recently, several other automated comparative modeling servers have also been developed, such as CPHmodels (5), 3D-JIGSAW (6), ModWeb (7) and ESyPred3D (8).

    Although so many automated comparative modeling servers are available, most of them do not work well on small SDPs for two reasons. Most of the automated servers are primarily designed for globular protein domains, making it difficult to discriminate small-sized SDPs from background noise. Taking as an example the sequence of alpha-conotoxin PnIA (9) (PDB id: 1PEN; 16 residues; 2 disulfide bridges in its structure), we note that both SWISS-MODEL and ModWeb report that they do not cover the modeling of sequences <25 or ?30 amino acid residues in length, respectively, while the other three servers state that no suitable templates can be identified for this sequence.

    The second reason is that SDPs have distinct characteristics from medium-sized and large globular proteins. They usually do not have a compact hydrophobic core, which is a major factor in stabilizing protein structure. Their side chains are more likely to be exposed to solvent and their conformations are more flexible. The 3D structures of small proteins are usually dominated by disulfide bridges, metal or ligand (according to SCOP classification) (10) and tend to bind or interact with large molecules. In small disulfide-rich proteins, the effects of disulfide bridges and constrained residues such as prolines are more significant than sequence similarity. As such, the comparative modeling rules for such proteins are highly specific and different from those adopted for large globular proteins. These distinct features require specific methods and datasets to be developed for the comparative modeling of SDPs.

    To address these problems, we have first developed special strategies and rules for large-scale automated comparative modeling of the entire family of conotoxins (L. Kong and S. Ranganathan, unpublished data). Subsequently these rules were extended to other SDPs. Here, we present SDPMOD, a comprehensive comparative modeling server that is designed specifically for SDPs with specialized rules and datasets.

    Korotina AS, Kriukova EV, Azeeva EA, Sheval'e AF, Utkin IuN, Tsetlin VI.(2003) [Sensitive nonradioactive screening method for compounds interacting with alpha7-cholinoreceptor] [Article in Russian] Bioorg Khim. 29(4)391-396.
    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, GSP Moscow, 117997 Russia.
    Abstract: A sensitive nonradioactive method for detection of substances interacting with the neuronal nicotinic acetylcholine alpha 7-type receptor (AChR) was proposed. The method uses biotinylated alpha-cobratoxin (Bt-CTX) and is based on the ability of the N-terminal ligand-binding extracellular domain (LBED) of AChR to interact with alpha-cobratoxin (CTX) as does the whole receptor. LBED was produced by heterologic expression of a gene fragment of the alpha 7 subunit of AChR from the rat brain in Escherichia coli cells sorbed on wells of a 96-well plate and incubated with Bt-CTX. The specifically bound Bt-CTX was determined by staining with streptavidin-peroxidase complex. The ability of other compounds to interact with alpha 7-AChR was checked according to the degree with which they inhibit Bt-CTX binding to LBED. Nicotine, carbamylcholine, d-tubocurarin, anabaseine, conotoxin ImI, and neurotoxin II were used as model compounds. The sensitivity of this method was comparable with that of the radioligand method (up to 10 pmol).

    KOSUGE & al., 1969. Conus gloriamaris Newly Obtained from the Philippines. 4pp., 9figs., in Japanese, English summ. Euro 0.70

    KOSUGE, 1981. Descriptions of 2 N.Sp. of the Genus Morum with Remarks on the Recent Species from Philippines; combined with: KOSUGE, 1981. Studies on the Collection of Mr. V. Dan (4) Descriptions of N.Sp. of the Genera Lyria, Conus & Fissidentalium. 8pp., 2pls. Euro 2.00

    KOSUGE, 1981. Descriptions of 3 N.Sp. of the Genus Latiaxis from Japan & Philippines; combined with: KOSUGE, 1981. Description of A N.Sp. of the Family Fasciolariidae from Philippines; &: KOSUGE, 1981. Notes on Newly Recorded Species of the Superfamily Conacea from Philippines with Descriptions of N.Sp. of the Genera Terebra, Conus & Glyphostoma; &:

    KOSUGE, 1981. Notes on the Family Triphoridae from Philippines; &: KOSUGE, 1981. Note on Conus sulcocastaneus Nom. Nov. 13pp., 3pls. Euro 3.20

    Kreienkamp, H.-J., Sine, S.M., Maeda, R.K. and Taylor, P. (1994) Glycosylation sites selectively interfere with alpha-toxin binding to the nicotinic acetylcholine receptor. J. Biol. Chem. 269: 8108-8114.
    [Abstract:Conus Magus, alpha-conotoxin MI, alpha 3/5 group, fish-hunting, Indo-Pacific]

    Kulak, J. M., Nguyen, T. A., Olivera, B. M. and McIntosh, J. M.(1977) a-Conotoxin MII blocks nicotine-stimulated dopamine release in rat striatal synaptosomes. J. Neuroscience 17 : 5263-5270..

    Kuei-Sen, T.H., Chiung-Chun H. and Ping-Chiang, L. (1996) Inhibition of calcium channels in rat hippocampal CA1 neurons by conantokin.Neurosci Lett , 220, 113-117..
    Abstract: Effects of conantokin-T, a 21 amino acid peptide toxin isolated from the fish-hunting cone snail Conus tulipa, on the high-voltage-activated Ca2+ channel currents were studied in acutely dissociated rat hippocampal CA1 neurons using whole-cell voltage clamp-recording technique with 5 mM Ba2+ as the charge carrier. Conantokin-T inhibited the whole-cell Ba2+ current (IBa) in a concentration-dependent manner. The nimodipine (20 muM) and omega-agatoxin-IVA (0.2 muM) block of IBa were abolished in the presence of conantokin-T (3 muM); however, conantokin-T (3 muM) did not affect the block of IBa induced by 3 muM omega-conotoxin-GVIA. These results indicate that conantokin-T is a potent but wide-spectrum Ca2+ channel antagonist.
    Kuryatov, A., Olale, F., Cooper, J., Choi, C., Lindstrom, J. (2000). Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses. Neuropharmacology 39: 2570-2590.
    Department of Neuroscience, University of Pennsylvania Medical School, 217 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104-6074, USA.
    Abstract: Many nicotinic acetylcholine receptor (AChR) subunits are known to be co-expressed with the alpha6 subunit in neurons. Because alpha6beta4 AChRs assemble inefficiently and alpha6beta2 AChRs not at all, more complex mixtures of human subunit cDNAs were tested for their abilities to form functional AChRs when expressed in Xenopus oocytes. alpha6beta4beta3 AChRs produced the largest and most consistent responses. alpha6alpha3beta2 AChRs exhibited reduced potency for ACh and increased potency and efficacy for nicotine compared to alpha3beta2 AChRs, but similar resistance to functional inactivation after prolonged exposure to nicotine. alpha6alpha4beta2 AChRs differed little in potency or efficacy for ACh or nicotine compared to alpha4beta2 AChRs, and had similarly high sensitivity to inactivation by prolonged exposure to nicotine. Co-expression of alpha6 and beta2 cRNAs resulted in large numbers of (3)H-epibatidine binding sites in the form of large aggregates but not in functional pentameric AChRs. Co-expression of alpha6, beta2, and alpha5 resulted in assembly of some functional pentameric AChRs. Chimeras with the large extracellular domain of alpha6 and the rest from either alpha3 or alpha4 efficiently formed functional AChRs. Thus, the extracellular domain of alpha6 efficiently assembles with beta2 to form ACh binding sites, but more C-terminal domains cause difficulties in forming pentameric AChRs. Chimeric alpha6/alpha3 and alpha6/alpha4 AChRs containing either beta2 or beta4 subunits were blocked by alpha-conotoxin MII which had previously been reported to be specific for alpha3beta2 AChRs.

    Lamthanh, H., Tremeau, O. and Menez, A. (1996) On the functionally important residues of alpha-conotoxin GI, as visited by L-alanine scanning. European Peptide Symposium, October 1996.

    Lang PM, Burgstahler R, Sippel W, Irnich D, Schlotter-Weigel B, Grafe P. (2003) Characterization of neuronal nicotinic acetylcholine receptors in the membrane of unmyelinated human C-fiber axons by in vitro studies. J Neurophysiol. 90: 3295-3303.
    Departments of Physiology and Anesthesiology and Friedrich-Baur-Institute, Ludwig-Maximilians University, 80336 Munich, Germany.

    Abstract: Application of acetylcholine to peripheral nerve terminals in the skin is a widely used test in studies of human small-fiber functions. However, a detailed pharmacological profile and the subunit composition of nicotinic acetylcholine receptors in human C-fiber axons are not known. In the present study, we recorded acetylcholine-induced changes of the excitability and of the intracellular Ca2+ concentration in C-fiber axons of isolated human nerve segments. In addition, using immunohistochemistry, an antibody of a subtype of nicotinic acetylcholine receptor was tested. Acetylcholine and agonists reduced the current necessary for the generation of action potentials in C fibers by > 5-Iodo-A-85380 > 1,1-dimethyl-4-phenylpiperazinium iodide > nicotine > cytisine > acetylcholine; choline had no effect. The epibatidine-induced increase in axonal excitability was blocked by mecamylamine and, less efficiently, by methyllycacontine and dihydro-beta-erythroidine. Many C-fiber axons were labeled by an antibody that recognizes the alpha5 subunit of nicotinic acetylcholine receptors. In summary, electrophysiological and immunohistochemical data indicate the functional expression of nicotinic acetylcholine receptors composed of alpha3, alpha5, and beta4 but not of alpha4/beta2 or of alpha7 subunits in the axonal membrane of unmyelinated human C fibers. In addition, the observations suggest that the axonal membrane of C fibers in isolated segments of human sural nerve can be used as a model for presumed cholinergic chemosensitivity of axonal terminals.

    Articles on cone shell toxins and other toxins at LA Times.

      Care at the end of life Different Drugs for Different Varieties of Pain; [Home Edition] Linda Marsa. Los Angeles Times. Los Angeles, Calif.: Aug 20, 2001. pg. S.8

      Going the natural root [Home Edition] JUDY FOREMAN. Los Angeles Times. Los Angeles, Calif.: Apr 2, 2001. pg. S.6

      Harvesting the seas Researchers Dive the Ocean Depths in Search of Organisms for New Drugs; [Home Edition] NORA ZAMICHOW. Los Angeles Times (pre-1997 Fulltext). Los Angeles, Calif.: Nov 2, 1992. pg. 3

      A Whole Pharma-Sea Out There? Research: Two San Diego scientists plumb the depths for inspiration in developing drugs for human ills.; [San Diego County Edition] NORA ZAMICHOW. Los Angeles Times (pre-1997 Fulltext). Los Angeles, Calif.: Oct 25, 1992.

      Oceans of HopeThe search for potent marine chemicals to treat pain and disease is steaming ahead. Drugs derived from aquatic creatures are making their way to the market.; [Home Edition] LINDA MARSA. Los Angeles Times. Los Angeles, Calif.: Feb 11, 2002. pg. S.1

    Lawand, N.B., Lu, Y. and Westlund, K.N. (1999) Nicotinic cholinergic receptors: potential targets for inflammatory pain relief. Pain. 80:291-299.
    Department of Anatomy and Neuroscience, The Marine Biomedical Institute, The University of Texas Medical Branch at Galveston, 77555-1069, USA.
    Abstract: We have shown previously that the development of hyperalgesia and inflammation associated with knee joint arthritis depends on interactions among various receptors in the central and peripheral nervous system in addition to the contribution of blood borne inflammatory mediators. In the present study, the involvement of spinal nicotinic cholinergic receptors in the modulation of inflammatory pain was evaluated using a model of acute arthritis in rats. Epibatidine (EP), a potent agonist for neuronal nicotinic acetylcholine receptors sharing similar structural and functional characteristics with acetylcholine and nicotine, has been used in this study. The physiological effects of EP on pain-related behaviors and inflammation were tested after administration to the dorsal horn via a microdialysis fiber. Knee joint inflammation was induced in rats by injecting a mixture of kaolin and carrageenan into the knee joint. Paw withdrawal latency to radiant heat was measured before and at 4, 5, 6, 7 and 8 h after induction of inflammation. The decrease in PWL in this arthritis model is indicative of secondary hyperalgesia. The extent of peripheral inflammation was also assessed by measuring knee joint circumference and temperature. Treatment of the spinal cord of animals with EP prior to induction of arthritis attenuated the development of heat hyperalgesia and resulted in a significant improvement of the animals' spontaneous pain-related behaviors. More interestingly, the knee joint circumference and temperature of these animals were also significantly lower than those of the control animals when measured at 8 h. Likewise, spinal administration of epibatidine after the development of hyperalgesia not only significantly attenuated the decrease in PWL, but prevented further increases in knee joint swelling and temperature. The antinociceptive effect of epibatidine was selectively blocked by the nicotinic receptor antagonist, mecamylamine. Joint circumference and temperature were not selectively altered by mecamylamine suggesting another mechanism involving non-nicotinic receptors in the spinal regulation of joint inflammatory responses. Collectively, these findings provide considerable evidence to suggest an important role for central nicotinic cholinergic receptors in the modulation of persistent pain and neurogenic inflammation mediated by events in the dorsal horn.

    Le Gall, F., Favreau, P., Benoit, E., Letourneux, Y. and Molgo, J. (1998) Repetitive and spontaneous acetylcholine release from motor nerve terminals induced by a neurotoxin isolated from Conus ermineus venom. J. Physiol.- Paris, 92: 456-458. .
    Abstract: Marine snails of the genus Conus are venomous animals classified according to their feeding behaviour into piscivorous, molluscivorous and vermivorous species. Several peptide toxins have been isolated from the venom of fish-hunting cone snails: alpha-conotoxins active on nicotinic receptors; mu-conotoxins which block voltage-dependant Na+ channel in skeletal muscle and omega-conotoxins which interact with voltage-gated Ca2+ channels subtypes. Each of these toxins potently block neuromuscular transmission in vertebrates producing flaccid muscle paralysis. Because of their specific actions on key elements of excitable cells and receptors, conotoxins have been widely used as tools for studying synaptic transmission mechanisms and for characterizing ion channels and receptor subtypes.The observation that the venom of the fish-hunting cone snail C. ermineus elicits prominent muscle contraction in fish prompted us to purify the toxin(s) responsible for the observed action of the venom and to characterize its mode of action on excitable membranes and neurotransmitter release from nerve terminals. The present communication reports that C. ermineus venom contains a neuropeptide named deltaA-EVIA (Mr, 3300 D) which selectively increases synaptic efficacy at the vertebrate neuromuscular junction by increasing the number of synaptic responses evoked by a single nerve stimulus as well as the spontaneous quantal acetylcholine release from motor nerve terminals through a sodium dependent mechanism. deltaA-EVIA, when applied to isolated frog nerve-muscle preparations (cutaneous pectoris) bathed in normal Ringer's solution causes a long-lasting spontaneous contraction of the muscle fibers which prevented stable intracellular recordings. In order to avoid muscle movements, excitation-contraction was uncoupled by formamide treatment. Intracellular recordings from formamide-treated junctions revealed that deltaA-EVIA (200 nM) induced repetitive action potentials in response to a single nerve stimulus. These action potentials were triggered by spontaneous and repetitive endplate potentials (EPPs) which could attain high frequencies (figure 1). This repetitive synaptic activity had variable duration, could last tens of seconds and was not or little modified by increasing Mg2+ concentration in the extracellular medium or by addition of (+)-tubocurarine (3 muM). Analysis of the quantal contents of EPPs, in preparations equilibrated with low Ca2+ (0.3 mM) and high Mg2+ (6 mM) Ringer's solution revealed that deltaA-EVIA (200 nM) did not modify the average number of quanta released during the first phasic EPP. Thus, it appears that the main effect of deltaA-EVIA is to alter the 1:1 input-output ratio of the neuromuscular junction. In other words, deltaA-EVIA induces a marked repetitive synchronous release of acetylcholine in response to a single nerve stimulus. Interestingly, the repetitive EPPs in a given train exhibited facilitation that could last tens of seconds.In addition, deltaA-EVIA (200 nM) after a delay of about 40 min increased spontaneous quantal acetylcholine release, recorded as miniature endplate potential (MEPP) frequency, in a nominally Ca2+ free medium supplemented with EGTA (2 mM). Such an enhancement of MEPP frequency could be either prevented or reversed by the sodium channel blocker, tetrodotoxin (1 muM). These results indicate that the increase of MEPP frequency caused by deltaA-EVIA is related to sodium entry into motor nerve endings. In conclusion, deltaA-EVIA isolated from C. ermineus venom constitutes a new excitotoxin that interacts with voltage-gated Na+ channels modifying nerve terminal excitability, neurotransmitter release and synaptic efficacy at the vertebrate neuromuscular junction.

    LE GALL & al., 1999. Biodiversity of the genus Conus: a rich source of bioactive peptides. 26pp., 7tabs., 2figs. (1col.fig.). Euro 4.45

    Lev Ram, V, Olivera, B, Levitan, I B. (1987). Conus Venom Alters Ionic Currents in Identified Aplysia Neurons. 17TH ANNUAL MEETING OF THE SOCIETY FOR NEUROSCIENCE, NEW ORLEANS, LOUISIANA, USA, NOVEMBER 16-21, 1987. SOC NEUROSCI ABSTR 13 2 1987 ASNEE Society for Neuroscience Abstracts 0190-5295 792.

    Lev-Ram, V, Olivera, B M, Levitan, I B. (1994). A toxin from the venom of the predator snail Conus textile modulates ionic currents in Aplysia bursting pacemaker neuron. Brain Research 640 1-2 1994 0006-8993 48-55. {Aplysia californica}

    Lewis, R.J. (2000) Ion channel toxins and therapeutics: from cone snail venoms to ciguatera. Ther Drug Monit.22:61-64.
    Centre for Drug Design and Development, The University of Queensland, Brisbane, Australia.
    Abstract: Ion channels are intimately linked to all neurotransmission and neurotransmitter release processes, but in disease states often contribute adversely to disease pathology. The diversity and distribution of ion channel types and subtypes being uncovered through the use of molecular biology and toxin probes present an exciting opportunity for the discovery of new, more selective drugs. Among ion channels targeted by cone shell venom peptides (conotoxins) are the voltage-sensitive sodium, calcium, and potassium channels which open and then close (inactivate) in response to membrane depolarization, and thus regulate neurotransmission and the neurotransmitter release process. Conotoxins also target ligand-gated ion channels, including the NMDA-glutamate channel and the nicotinic acetylcholine receptor channel. The diversity of subtypes, especially those subtypes upregulated in disease states, makes ion channels a rapidly expanding therapeutic area. Conotoxins represent some of the most selective inhibitors of ion channel subtypes and have often been used as the defining ligand. In this overview, the structures and therapeutic potential of conotoxins active at ion channels are highlighted. The activity and structures are then contrasted with ciguatoxins, which are responsible for the food poisoning known as ciguatera. A universal liquid chromatography/mass spectrometry approach to the detection of these classes of toxins is briefly discussed.

    Lewis, R.J. (2004) Conotoxins as selective inhibitors of neuronal ion channels, receptors and transporters. IUBMB Life. 56: 89-93.
    Institute for Molecular Biosciences, The University of Queensland, 4072, Australia. r.lewis@imb.uq.edu.au
    Abstract: Cone snails have evolved a vast array of peptide toxins for prey capture and defence. These peptides are directed against a wide variety of pharmacological targets, making them an invaluable source of ligands for studying the properties of these targets in normal and diseased states. A number of these peptides have shown efficacy in vivo, including inhibitors of calcium channels, the norepinephrine transporter, nicotinic acetylcholine receptors, NMDA receptors and neurotensin receptors, with several having undergone pre-clinical or clinical development for the treatment of pain.

    Lewis, R.J., Bingham, J.P., Jones, A., Alewood, P.F., Andrews, P.R. (1994) Drugs from the peptide venoms of marine cone shells. Australas Biotechnol. 4: 298-300. Review.
    Drug Design and Development (3D) Centre, Gehrmann Laboratories, University of Queensland, St Lucia.
    Abstract: Australian cone shell venoms are being investigated as an exciting new source of bioactive peptides as part of a new collaborative project between the 3D Centre and AMRAD. Initial studies have already revealed a number of new and novel acting peptides amongst the hundred or so small, heavily constrained peptides present in the venom of each cone shell. The aim of the project is to develop peptidomimetic drugs based on a selection of these native peptides.

    Lewis, R.J. (1), Smith, M. (2), Alewood, D.(1) and Drinkwater, R. (1) (2004) Anti-allodynic effects of Xen2174 in rats with neuropathy. Abstract in: "Neuropathic Pain - Changing paradigms in diagnosis and treatment". Madrid, Spain, May 13-16, 2004. [NeuPSIG - An International Congress of NeuPSIG, The Special Interest Group on Neuropathic Pain in the International Association for the Study of Pain (IASP) ]
    (1) School Of Pharmacy, The University Of Queensland, Brisbane, Australia;
    (2) Xenome Ltd, Brisbane, Australia;
    Abstract:Background and Aims: chi-Conopeptides are selective, non-competitive inhibitors of the noradrenaline transporter. This study was designed to quantify the anti-allodynic effects of the synthetic chi-conopeptide, Xen2174, when administered by the intrathecal (i.t.) route to rats with neuropathic pain. Xen2174 effects were compared with i.t. morphine. Methods: Adult male Sprague-Dawley rats were deeply anaesthetized with ketamine (80 mg/kg i.p.) and xylazine (8 mg/kg i.p.), and four loose ligatures were tied around the sciatic nerve to induce a chronic constriction injury (CCI). On day 11 following CCI-surgery, rats were again anaesthetized with ketamine/xylazine and an i.t. cannula inserted. On day 14 post-CCI surgery, rats received a bolus i.t. injection of Xen2174 (0.2-30 nmol), morphine (3.5-50 nmol) or saline (control rats) and tactile allodynia, the distinguishing feature of neuropathic pain, was quantified using calibrated von Frey filaments (2-20 g). Results: The i.t. administration of bolus doses of Xen2174 produced dose-dependent relief of tactile allodynia with a peak anti-allodynic effect observed at ~ 1 h post-dosing and a duration of action of up to ~ 48 h at higher doses. However, in contrast to the maximal responses evoked by the higher doses of i.t. Xen2174 (ED50 = 15.1 nmol), i.t. morphine (ED50 = 8.9 nmol) produced only a sub-maximal response in CCI-rats, indicating a pronounced ceiling effect. Conclusions: Xen2174 administered i.t. is efficacious for the relief of tactile allodynia in a rat model of neuropathic pain. This results highlights the important role in pain control played by noradrenaline released from descending inhibitory pathways. Xen2174 is being developed for i.t. administration to patients with intractable neuropathic pain.

    Lewis, T.M., Harkness, P.C., Sivilotti, L.G., Colquhoun, D. and Millar, N.S. (1997) The ion channel properties of a rat recombinant neuronal nicotinic receptor are dependent on the host cell type. J Physiol. 505: 299-306.
    Wellcome Laboratory for Molecular Pharmacology, Department of Pharmacology, University College London, UK.
    Abstract: 1. A stable mammalian cell line (L-alpha 3 beta 4) has been established which expresses the cloned rat neuronal nicotinic acetylcholine receptor (nAChR) subunits alpha 3 and beta 4, which are the most abundant in autonomic ganglia. Ion channel properties of nAChRs expressed in L-alpha 3 beta 4 cells were investigated by single-channel and whole-cell recording techniques, and compared with both rat alpha 3 beta 4 nAChRs expressed in Xenopus oocytes, and endogenous nicotinic receptors in rat superior cervical ganglion (SCG) neurones, using identical solutions for all cell types. 2. Acetylcholine (ACh) caused activation of single ion channel currents with a range of amplitudes. Some channels had high conductances (30-40 pS), and relatively brief lifetimes; these resembled the predominant native channel from SCG. Other channels had low conductances (20-26 pS) and long bursts of openings which were quite unlike native channels, but which were similar to channels formed by alpha 3 beta 4 in oocytes. Both types often occurred in the same patch. 3. Cytisine was about 3 times more potent than ACh (low-concentration potency ratio) in L-alpha 3 beta 4 cells, which is not dissimilar to the 5-fold potency ratio found in both SCG and oocytes, whereas 1,1-dimethyl-4-phenylpiperazinium (DMPP) was less potent than ACh in some cells (as in the oocyte), but more potent in others (as in SCG). 4. While the channels expressed in L-alpha 3 beta 4 cells do not mimic exactly those expressed in rat SCG, they differ considerably from the same subunit combination expressed in oocytes. Larger conductance, SCG-like channels were detected frequently in L-alpha 3 beta 4, but were rarely, if ever, seen in oocytes injected with alpha 3 and beta 4 mRNA. Our results indicate that ion channel properties such as single-channel conductance can be influenced by the choice of heterologous expression system.

    Liang YC, Huang CC, Hsu KS, Takahashi T. (2003) Cannabinoid-induced presynaptic inhibition at the primary afferent trigeminal synapse of juvenile rat brainstem in slice. J Physiol. 2003 Dec 12 [Epub ahead of print].

    Abstract: Systemic or intraventricular administration of cannabinoids causes analgesic effects, but relatively little is known for their cellular mechanism. Using brainstem slices with the mandibular nerve attached, we examined the effect of cannabinoids on glutamatergic transmission in superficial trigeminal caudal nucleus of juvenile rats. Exogenous cannabinoid receptor agonist WIN 55,212-2 (WIN), as well as the endogenous agonist anandamide, hyperpolarized trigeminal caudal neurons and depressed the amplitude of excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) monosynaptically evoked by stimulating mandibular nerves in a concentration-dependent manner. The inhibitory action of WIN was blocked or fully reversed by the CB1 receptor antagonist SR 141716A. WIN had no effect on the amplitude of miniature excitatory postsynaptic currents (mEPSCs) recorded in the presence of tetrodotoxin or cadmium. The inhibitory effect of WIN on EPSCs was greater for those with longer synaptic latency, suggesting that cannabinoids have a stronger effect on C- fibre EPSPs than on Ad-fibre EPSPs. Ba2+ (100 micro M) blocked the hyperpolarizing effect of cannabinoids, but did not affect their inhibitory effect on EPSPs. The N- type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTX) occluded the WIN-mediated presynaptic inhibition, whereas the P/Q-type Ca2+ channel blocker omega-agatoxin TK (omega-Aga) had no effect. These results suggest that cannabinoids preferentially activate CB1 receptors at the nerve terminal of small- diameter primary afferent fibres. Upon activation, CB1 receptors may selectively inhibit presynaptic N-type Ca2+ channels and exocytotic release machinery, thereby attenuating the transmitter release at the trigeminal nociceptive synapses.

    Likeman R (1975) Letter: Turtle meat and cone shell poisoning. P N G Med J 1975; 18(2): 125-126.

    LINNAEUS, C., 1758. Systema Naturae per Regna Tria Naturae, 10th ed.

    Liltved, W.R. and Millard, V.G. (1989) Conidae of South Africa, The Strandloper, Jan/Jun 225: 2-12

    Livett, B.G. (1997) Beauty and the Beast: Molecular Prospecting for Novel Drugs from the Sea Communicated to The Royal Society of Victoria, Thursday 13 March, 1997 [Abstract: Reviews research on conotoxins, focusing on that underway in Dr. Livett's laboratory, Dept. of Biochemistry and Molecular Biology, University of Melbourne, Victoria, Australia]

    Livett, B.G.(2002) An "Internet Interview" with Bruce Livett (Interviewer, Eduardo Moreira) American Conchologist 30: 5 & 14.

    Loch, I. 1974. Feeding of Conus eburneus. Australian Shell News 6: 10.

    Loch, I. 1977. Untitled Note (Conus textile). Australian Shell News 19: 6.

    Loch, I. 1987. Untitled Note (Conus crocatus). Townsville Shell Club 11: 8-9.

    Loch, I. 1987. Untitled Note (Cairns area Conus). Cairns Shell News 35: 3.

    Loch, I. 1990. Conus adami. Australian Shell News 69: 4.

    Loch, I. 1994. Conus exiguus. Australian Shell News, 87:7.

    Lopez-Rodriguez M.L.; Viso A.; Ortega-Gutierrez S. (2003) VR1 Receptor Modulators as Potential Drugs for Neuropathic Pain. Mini Reviews in Medicinal Chemistry 3: 729-748
    Abstract:The involvement of VR(1) in the endogenous pain signalling has converted this receptor into a promising therapeutic target for the development of a new family of potent analgesics devoid of the shortcomings of other analgesics commonly used. The desensitisation induced after VR(1) activation points to the utility of VR(1) agonists for the treatment of various nociceptive disorders including mitigation of neuropathic pain, inhibition of neurogenic inflammation and suppression of urinary bladder hyperreflexia, whereas VR(1) antagonists have been described as valuable agents for the treatment of inflammatory hyperalgesia and pain. Structure of the main classes of VR(1) ligands developed to date, their molecular mechanisms of action and their promising utility for the management of diverse nociceptive alterations, specially neuropathic pain, are discussed in this review. PMID: 14529514 [PubMed - in process]

    Lopez-Vera, E., Heimer de la Cotera, E.P., Maillo, M., Riesgo-Escovar, J.R., Olivera B.M. and Aguilar, M.B. (2004) A novel structural class of toxins: the methionine-rich peptides from the venoms of turrid marine snails (Mollusca, Conoidea). Toxicon.43: 365-374.
    Laboratory of Marine Neuropharmacology, Institute for Neurobiology, Universidad Nacional Autonoma de Mexico, Queretaro 76230, Mexico.

    Abstract:The objective of this investigation was to purify and characterize polypeptides from the venom ducts of the turrid snails Polystira albida and Gemmula periscelida (superfamily: Conoidea, family: Turridae), collected in Mexican waters. Venoms of other groups in the superfamily (family: Conidae, genus: Conus) have peptide toxins ('conotoxins'), but no venom components have been characterized from any turrid species. Crude venoms were fractionated using reversed-phase high performance liquid chromatography, and one major component from each venom was characterized. In contrast to most conotoxins, the polypeptides characterized contain a high proportion of Met, Tyr and Arg residues, and few, if any, Cys residues. The two peptides had some regions of homology, but were not significantly similar to other peptides. Both peptides are predicted to contain alpha-helical structures, and the peptide from P. albida is predicted to form a coiled-coil motif. This structural motif could provide conformational stability for these turrid venom components ("turritoxins"), which in the case of conotoxins is primarily achieved by disulfide bonds. Thus, the first turritoxins characterized are strikingly different from the conotoxins, suggesting divergent biochemical strategies in the venoms of different major groups included in the superfamily Conoidea.

    LORENZ, 2005. An overlooked species of Conus.

    Loughnan, M., Bond, T., Atkins, A., Cuevas, J., Adams, D.J., Broxton, N.M., Down, J.G., Livett, B.G., Jones, A., Alewood, P.F. and Lewis, R.J. (1998) alpha-Conotoxin EpI, a Novel Sulfated Peptide from Conus episcopatus that Selectively Targets Neuronal Nicotinic Acetylcholine Receptors" J.Biol.Chem. 273: 15667-15674.
    Centre for Drug Design and Development, The University of Queensland, St. Lucia Queensland 4067, Australia.
    Abstract:We have isolated and characterized alpha-conotoxin EpI, a novel sulfated peptide from the venom of the molluscivorous snail, Conus episcopatus. The peptide was classified as an alpha-conotoxin based on sequence, disulfide connectivity, and pharmacological target. EpI has homology to sequences of previously described alpha-conotoxins, particularly PnIA, PnIB, and ImI. However, EpI differs from previously reported conotoxins in that it has a sulfotyrosine residue, identified by amino acid analysis and mass spectrometry. Native EpI was shown to coelute with synthetic EpI. The peptide sequence is consistent with most, but not all, recognized criteria for predicting tyrosine sulfation sites in proteins and peptides. The activities of synthetic EpI and its unsulfated analogue [Tyr15]EpI were similar. Both peptides caused competitive inhibition of nicotine action on bovine adrenal chromaffin cells (neuronal nicotinic ACh receptors) but had no effect on the rat phrenic nerve-diaphragm (muscle nicotinic ACh receptors). Both EpI and [Tyr15]EpI partly inhibited acetylcholine-evoked currents in isolated parasympathetic neurons of rat intracardiac ganglia. These results indicate that EpI and [Tyr15]EpI selectively inhibit alpha3beta2 and alpha3 beta4 nicotinic acetylcholine receptors.

    Lukas RJ, Changeux JP, Le Novere N, Albuquerque EX, Balfour DJ, Berg DK, Bertrand D, Chiappinelli VA, Clarke PB, Collins AC, Dani JA, Grady SR, Kellar KJ, Lindstrom JM, Marks MJ, Quik M, Taylor PW, Wonnacott S. (1999)International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol Rev. 51, 397-401. Review.

    Lynch SS, Cheng CM, Yee JL. (2006) Intrathecal ziconotide for refractory chronic pain. Ann Pharmacother. 2006 Jul-Aug;40(7-8):1293-300. Epub 2006 Jul 18. Review.
    Department of Clinical Pharmacy, University of California, San Francisco, 94143, USA. lynchs@pharmacy.ucsf.edu


    Abstract: OBJECTIVE: To describe the pharmacology, efficacy, and safety of ziconotide for treatment of severe chronic pain in patients who are candidates for intrathecal therapy. DATA SOURCES: A PubMed/MEDLINE search (1966-June 2006) was conducted using the terms ziconotide, Prialt, and SNX-111. Manufacturer-provided data, the Food and Drug Administration medical review of ziconotide, and abstracts presented at American Pain Society meetings (2001-2006) were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Human studies evaluating the efficacy and safety of ziconotide for the treatment of chronic pain were considered. Animal data were excluded. DATA SYNTHESIS: Ziconotide is the first and only neuronal-type (N-type) calcium-channel blocker. Ziconotide must be administered intrathecally via continuous infusion. A programmable implanted variable-rate microinfusion device, or an external microinfusion device and catheter must be utilized. In double-blind, placebo-controlled studies, ziconotide significantly improved patient perception of pain from baseline to the end of the study periods, which ranged from 11 to 21 days. Patients enrolled in clinical trials were intolerant of or refractory to other treatment modalities. There have been no studies that directly compared ziconotide with other intrathecal or systemic analgesics. Key ziconotide-related adverse events are neuropsychiatric, including depression, cognitive impairment, and hallucinations; depressed levels of consciousness; and elevation of creatine kinase levels. Ziconotide is also associated with a risk of meningitis due to possible contamination of the microinfusion device. CONCLUSIONS: Ziconotide is a therapeutic option for treatment of severe chronic pain in patients who have exhausted all other agents, including intrathecal morphine, and for whom the potential benefit outweighs the risks of serious neuropsychiatric adverse effects and of having an implanted device. Further studies are needed to determine the comparative efficacy of ziconotide and other pain therapies.

    McIntosh, J.M., Azam, L., Staheli, S., Dowell, C., Lindstrom, J.M., Kuryatov, A., Garrett, J.E., Marks, M.J. and Whiteaker, P. (2004) Analogs of {alpha}-Conotoxin MII Are Selective for {alpha}6-Containing Nicotinic Acetylcholine Receptors. Mol Pharmacol. 65: 944-952.
    Abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) both mediate direct cholinergic synaptic transmission and modulate synaptic transmission by other neurotransmitters. Novel ligands are needed as probes to discriminate among structurally related nAChR subtypes. alpha-Conotoxin MII, a selective ligand that discriminates among a variety of nAChR subtypes, fails to discriminate well between some subtypes containing the closely related alpha3 and alpha6 subunits. Structure-function analysis of alpha-conotoxin MII was performed in an attempt to generate analogs with preference for alpha6-containing [alpha6(*) (asterisks indicate the possible presence of additional subunits)] nAChRs. Alanine substitution resulted in several analogs with decreased activity at alpha3(*) versus alpha6(*) nAChRs heterologously expressed in Xenopus laevis oocytes. From the initial analogs, a series of mutations with two alanine substitutions was synthesized. Substitution at His9 and Leu15 (MII[H9A;L15A]) resulted in a 29-fold lower IC(50) at alpha6beta4 versus alpha3beta4 nAChRs. The peptide had a 590-fold lower IC(50) for alpha6/alpha3beta2 versus alpha3beta2 and a 2020-fold lower IC(50) for alpha6/alpha3beta2beta3 versus alpha3beta2 nAChRs. MII[H9A;L15A] had little or no activity at alpha2beta2, alpha2beta4, alpha3beta4, alpha4beta2, alpha4beta4, and alpha7 nAChRs. Functional block by MII[H9A;L15A] of rat alpha6/alpha3beta2beta3 nAChRs (IC(50) = 2.4 nM) correlated well with the inhibition constant of MII[H9A;L15A] for [(125)I]alpha-conotoxin MII binding to putative alpha6beta2(*) nAChRs in mouse brain homogenates (K(i) = 3.3 nM). Thus, structure-function analysis of alpha-conotoxin MII enabled the creation of novel selective antagonists for discriminating among nAChRs containing alpha3 and alpha6 subunits.

    McIntosh, J.M. and Jones, R.M. (2001) Cone venom - from accidental stings to deliberate injection. Toxicon 39: 1447 - 1451.
    [Abstract:[Cone snails have long been of note due to their colorful shells and deadly venom. Over the years, a number of people who have encountered these molluscs have been injured or killed by their sting. Biochemical analysis of the venom components has revealed a plethora of peptides and proteins that target a variety of receptors and ion channels. Pharmaceutical companies are now utilizing the selectivity and potency of Conus-derived peptides to develop novel medications for pain, epilepsy and other disorders.]

    McIntosh, M., Cruz, L.J, Hunkapiller, M.W., Gray, W.R. and Olivera, B.M. (1982) Isolation and structure of a peptide toxin from the marine snail Conus magus. Arch. Biochem. Biophys. 218: 329-334.
    [Abstract:Conus magus , alpha-conotoxin MI, alpha 3/5 group, fish-hunting, Indo-Pacific]

    McIntosh, J.M., Santos, A.D. and Olivera, B.M. (1999) Conus peptides targeted to specific nicotinic acetylcholine receptor subtypes. Annual Review of Biochemistry Vol. 68 59-88.

    McIntosh, J. M., Yoshikami, D., Mahe, E., Nielsen, D.B., Rivier, J.E., Gray, W.R., and Olivera, B.M. (1994). A nicotinic acetylcholine receptor ligand of unique specificity, alpha-conotoxin ImI. J.Biol. Chem. 269: 16733-16739.
    [Abstract:[Conus imperialis, alpha-conotoxin ImI, alpha 3/5 group, non-fish hunting, Indo-Pacific]

    McManus, O.B. and Musick, J.R. (1985) Postsynaptic block of frog neuromuscular transmission by conotoxin GI. J. Neurosci. 5: 110-116.
    [Abstract: conotoxins block neuromuscular transmission in vitro]

    Marshall, I.G. and Harvey, A.L. (1990) Selective neuromuscular blocking properties of alpha-conotoxins in vivo. Toxicon 28: 231-234.
    [Abstract:Conotoxin GI and MI specific for neuromuscular system of cat, GI/MI/vecuronium/dTC = 50/20/10/1, vecuronium, neostigmine]

    Malishenko, A. (1994). Conotoxins: a case for their cause of the rapid evolutionary radiation of Conus.

    [Abstract: Conotoxins are some of the most efficiently designed poisons known to man. They are proving to be a valuable tool in medical research...There is a very interesting adaptive radiation theory hidden in the sequences of the DNA of these small (but definitely not innocuous) cone snails which is just waiting to be unraveled by some curios scientist !!]

    Malmberg, A.B., Gilbert, H., McCabe, R.T. and Basbaum, A.I. (2003) Powerful antinociceptive effects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T.Pain 101: 109-117. .
    Abstract: Subunit non-selective N-methyl-d-aspartate (NMDA) receptor antagonists reduce injury-induced pain behavior, but generally produce unacceptable side effects. In this study, we examined the antinociceptive and motor effects of cone snail venom-derived peptides, conantokins G and T (conG and conT), which are selective inhibitors of the NR2B or NR2A and NR2B subtypes of the NMDA receptor, respectively. We tested the effects of conG and conT in models of tissue (formalin test), nerve injury (partial sciatic nerve ligation) and inflammation-induced (intraplantar Complete Freund's Adjuvant; CFA) pain in mice. In the formalin test, intrathecal (i.t.) conG or conT suppressed the ongoing pain behavior (ED50 and 95% confidence intervals (CI), 11 (7-19) and 19 (11-33), respectively) at doses that were 17-27 times lower than those required to impair motor function (accelerating rotarod treadmill test: ED50 and 95% CI, 300 (120-730) and 320 (190-540) pmol, respectively). By comparison, SNX-111, an N-type voltage-sensitive calcium channel antagonist that is also derived from cone snail venom, produced significant motor impairment at a dose (3.0pmol, i.t.) that was only partially efficacious in the formalin test. Furthermore, conG reversed the allodynia produced by nerve injury, with greater potency on thermal (ED50 and 95% CI, 24 (10-55) pmol) than on mechanical allodynia (59 (33-105) pmol). Finally, a single dose of conG (100pmol, i.t.) also reduced CFA-evoked thermal and mechanical allodynia. Taken together, these results demonstrate that conantokins exhibit potent antinociceptive effects in several models of injury-induced pain. The study supports the notion that drugs directed against subtypes of the NMDA receptor, by virtue of their reduced side-effect profile, hold promise as novel therapeutic agents for the control of pain.

    Mansvelder, H.D., Stoof, J.C. and Kits, K.S. (1996) Dihydropyridine block of omega-agatoxin IVA- and omega-conotoxin GVIA-sensitive Ca2+ channels in rat pituitary melanotropic cells. Europ. J. Pharmacol. : 311, 293-305. .
    Abstract: High voltage-activated Ca2+ currents in rat melanotropic cells consist of a sustained and an inactivating component. In this study the pharmacological properties of the high voltage-activated Ca2+ channels underlying these components are investigated with whole-cell recordings. We report that melanotropes express four pharmacologically distinct high voltage-activated Ca2+ channels. Non-inactivating L-type channels account for 35% of the total high voltage-activated channel population. These channels have a very high affinity for the dihydropyridine nimodipine (EC50 3 pM). The cone snail toxin omega-conotoxin GVIA irreversibly blocked an inactivating high voltage-activated component which accounted for 26% of the total whole-cell high voltage-activated Ca2+ current. The spider toxin omega-agatoxin IVA reversibly blocked an additional 31% of the total high voltage-activated current. The current blocked by omega-agatoxin IVA was not homogenous and consisted of a sustained component with a high affinity for omega-agatoxin IVA (< 10 nM) and an inactivating current with a low affinity for omega-agatoxin IVA (~ 100 nM). Both the omega-agatoxin IVA and omega-conotoxin GVIA-blocked currents were very sensitive to nimodipine and nitrendipine with a half maximal block at 200-500 nM. 10 muM nimodipine blocked 70% of the omega-conotoxin GVIA-sensitive current and 90% of the omega-agatoxin IVA-sensitive current. Thus, omega-conotoxin GVIA- and omega-agatoxin IVA-sensitive high voltage-activated Ca2+ channels in melanotropes have an unusual high affinity for dihydropyridines compared to N-, P-, and Q-type channels in other preparations

    Marsh H (1971) The caseinase activity of some vermivorous cone shell venoms. Toxicon 1971; 9(1): 63-67.

    Martinez A. (2003) Preface. [Hot topic: Neuropathic Pain: Some Clues for the Future] Mini Reviews in Medicinal Chemistry 3: i.
    Abstract:People usually think of pain as having some physical cause. Get rid of the cause, and the pain goes away. However, nerves themselves can also generate pain, and this pain often doesn't go away easily. It is called neuropathic pain (from the Greek neuro, meaning nerves, and pathy, meaning abnormality). It can be puzzling and frustrating for people who have it and for doctors who treat it.
    Currently there is no proven treatment to prevent or cure neuropathic pain, but recent research has seen great progress in understanding its causes and in finding new drugs that promise great benefit.
    The first goal of this monographic issue is to review current knowledge of the targets, mechanisms, new drugs and treatments of neuropathic pain and prospects for the future with the aim of helping the scientific community in the search for effective therapies for this widespread disability.
    Dr. J.E. Banos and co-workers summarise the current understanding of the potential targets for neuropathic pain drug design and / or intervention in their complete concise revision.
    The state-of-the-art of the new drugs for neuropathic pain from a medicinal chemistry point of view is considered by the group of Dr. M.L. Lopez in its review focused on VR1 receptor modulators, Dr. A. Ferrer-Montiel et al., describing excellent analysis of small molecules targeting the NMDA receptor, my colleagues Drs. S. Morales and L. Rubio, focusing on AMPA glutamate receptor, and Dr. P. Goya and co-workers shedding light on the progress towards cannabinoids and neuropathic pain.

    Antidepressant drugs that have been used for over 30 years to cure neuropathic pain were accurately update by Drs. C. Mattia and F. Coluzzi.
    Finally, the oceans hold further promising compounds that might lead to new drugs. Conotoxins obtained from the predatory snails of the genus Conus probably describe a new era in the future treatment of neuropathic pain. A brief introduction of conotoxins by my colleague Diana Alonso precedes the complete table prepared by Dr. B. Livett and co-workers, focusing on therapeutic conopeptides. All the drugs belonging to the conopeptide family currently developing for treatment of neuropathic pain are described herein.
    I am very grateful to all the above-mentioned contributors for their excellent work and their willingness in the prompt submission of their manuscript. I signally hope readers will enjoy this issue and will find new clues to accelerate their own research
    Keywords: neuropathic pain; antidepressant; new antidepressant drugs; antinociception; mechanism of action; clinical trials
    Document Type: Book review ISSN: 1389-5575

    Martinez, J.S., Olivera, B.M., Gray, W.R., Craig, A.G., Groebe, D.R., Abramson, S.N. and McIntosh, J.M. (1995) alpha-conotoxin EI, a new nicotinic acetylcholine receptor antagonist with novel selectivity. Biochemistry 34: 14519-14526.

    [Conus erminius , alpha-conotoxin EI, alpha 4/7 group, fish-hunting, Atlantic]
    Abstract: We report the isolation and characterization of a novel nicotinic acetylcholine receptor (nAChR) ligand. The toxin is an 18 amino acid peptide and is the first reported alpha-conotoxin from an Atlantic fish-hunting Conus. The peptide was purified from the venom of Conus ermineus and is called alpha-conotoxin EI. The sequence diverges from that of previously isolated alpha-conotoxins. We demonstrate that this structural divergence has functional consequences. In Torpedo nAChRs, alpha-conotoxin EI selectively binds the agonist site near the alpha/delta subunit interface in contrast to alpha-conotoxin MI which selectively targets the alpha/gamma agonist binding site. In mammalian nAChRs alpha-conotoxin EI shows high affinity for both the alpha/delta and alpha/gamma subunit interfaces (with some preference for the alpha/delta site), whereas alpha-conotoxin MI is highly selective for the alpha/delta ligand binding site. The sequence of the peptide is: Arg-Asp-Hyp-Cys-Cys-Tyr-His-Pro-Thr-Cys-Asn-Met-Ser-Asn-Pro-Gln-Ile-Cys- NH2, with disulfide bridging between Cys4-Cys10 and Cys5-Cys18, analogous to those of previously described alpha-conotoxins. This sequence has been verified by total chemical synthesis. Thus, alpha-conotoxin EI is a newly-available tool with unique structure and function for characterization of nAChRs.]

    Charles Marwick (1998) Nature's agents help heal humans - some now take steps to reciprocate.(Medical News & Perspectives) . JAMA, The Journal of the American Medical Association, 279: 1679-1682. .
    Abstract: Scientists learned about research on drugs found in natural sources at a May, 1998 conference in New York. A chemical produced by the skin of the Ecuadoran frog is an analgesic, or painkiller, that is 30 to 70 times more powerful than morphine and has few side effects. Other researchers are focusing on peptides from the venom of the cone snail, which could also be used as analgesics. Many of the peptides block only one type of nerve cell receptor and would therefore have few side effects. Research on viper venom has isolated proteins that can prevent blood clotting.

    Massilia GR, Eliseo T, Grolleau F, Lapied B, Barbier J, Bournaud R, Molgo J, Cicero DO, Paci M, Schinina ME, Ascenzi P, Polticelli F. (2003) Contryphan-Vn: a modulator of Ca2+-dependent K+ channels. Biochem Biophys Res Commun. 303 :238-246.
    Abstract: Contryphan-Vn is a D-tryptophan-containing disulfide-constrained nonapeptide isolated from the venom of Conus ventricosus, the single Mediterranean cone snail species. The structure of the synthetic Contryphan-Vn has been determined by NMR spectroscopy. Unique among Contryphans, Contryphan-Vn displays the peculiar presence of a Lys-Trp dyad, reminiscent of that observed in several voltage-gated K(+) channel blockers. Electrophysiological experiments carried out on dorsal unpaired median neurons isolated from the cockroach (Periplaneta americana) nerve cord on rat fetal chromaffin cells indicate that Contryphan-Vn affects both voltage-gated and Ca(2+)-dependent K(+) channel activities, with composite and diversified effects in invertebrate and vertebrate systems. Voltage-gated and Ca(2+)-dependent K(+) channels represent the first functional target identified for a conopeptide of the Contryphan family. Furthermore, Contryphan-Vn is the first conopeptide known to modulate the activity of Ca(2+)-dependent K(+) channels.

    Mathur, V.S. (2000) Ziconotide: A new pharmacological class of drug for the management of pain. Seminars in Anesthesia, Perioperative Medicine and Pain, Vol. 19, Issue 2, June 2000, Pages 67-75.

    Mattia C.; Coluzzi F. (2003) Antidepressants in Chronic Neuropathic Pain. Mini Reviews in Medicinal Chemistry 3: 773-784
    Abstract:This review presents available clinical studies and new insights into mechanisms of analgesic effect and possible new routes of administration of antidepressant drugs. Older TCAs continue to be superior treatments. We focused on recent findings on newer antidepressants as analgesics. Their use should be supported by further controlled trials. PMID: 14529518 [PubMed - in process]

    Melentis J.K.(1970). The Conidae of Pylos.
    In 8ˇ, offp., pp. 28 con 2 tav. e 9 figs. [in greco con breve riassunto in tedesco] (Keywords: SHELLS FOSSIL PALEONTOLOGY GEOLOGY)

    Menzler S, Bikker JA, Suman-Chauhan N, Horwell DC. (2000) Design and biological evaluation of non-peptide analogues of omega-conotoxin MVIIA. Bioorg Med Chem Lett. 10: 345-347.
    Abstract: Omega-conotoxin MVIIA, a highly potent antagonist of the N-type voltage sensitive calcium channel, has shown utility in several models of pain and ischemia. We report a series of three alkylphenyl ether based analogues which mimic three key amino acids of the toxin. Two of the compounds have been found to exhibit IC50 values of 2.7 and 3.3 microM at the human N-type voltage sensitive calcium channel.

    Mermod, G., (1947). Catalogue des Types et des exemplaires de Cones figures ou decrits par Hwass, Bruguiere, Lamarck, De Lessert, Kiener et Chenu, se trouuvant au Musee de Geneve. Revue Suisse de Zoologie, 54 (5) 155-217. (Keywords: If you are looking for Conidae described by Hwass in Bruguiere then you should consult this book)

    Millard,V.G. and Freeman, D. (1979). Conidae of South Africa, The Strandloper, Apr/May 195:2-11

    Miljanich, G.P. (2004) Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem. 2004 Dec;11(23):3029-3040.
    Elan Pharmaceuticals, Inc., 7475 Lusk Boulevard, San Diego, CA 92121, USA. george.miljanich@elan.com

    Abstract: Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.

    Monteiro, A., Tenorio, J. M. & Poppe, G. T. (2004?) A Conchological Iconography The family Conidae - The W. African & Mediterranean species of Conus by A. Monteiro, J. M. Tenorio & G. T. Poppe; with a contribution by E. Rolan 2+102 pp., 10 + 104 figs., 97 maps, 4 b/w pls, 164 colour pls. Loose Leaf 4to.

    Moolenbeek & al., 1982. Conus pusio & C. melvilli. 4pp., 3figs. Hfl. 1.25

    Moolenbeek, R.G. (1986). Conidae of the Chesterfield Isls, with description of C.luciae n.sp. 6pp., 6figs., 1tab. Hfl. 2.00

    Moolenbeek, R. G. (1988). Notes on Australian Conidae Conus sydneyensis and Conus gabelishi. Gloria Maris, 27(1)9-13.

    Moolenbeek, R.G. (??) : Conus (Lilliconus) kuiperi n.sp., from the Sultanate of Oman. 83

    Morales-Alcelay S.; Rubio L.; Martinez A. (2003) AMPA Glutamate Receptors and Neuropathic Pain. Mini Reviews in Medicinal Chemistry 3: 757-763
    Abstract:Glutamate receptors are implicated in many actions in the central nervous system, as an excitatory amino acid, and one of the more relevant is its role in excitotoxicity. Apart from this, it also has a role as pro-nociceptive agent, so that antagonizing its actions could be of interest for developing new analgesic agents. Furthermore, between the analgesics agents, it is of outstanding interest the fact that there is no specific therapy against the neuropathic pain, and glutamate receptor subunits have elicited as new potential targets for this disturbance. PMID: 14529516 [PubMed - in process]

    Moreira, E. (2002) An "Internet Interview" with Bruce Livett. American Conchologist 30: 5 & 14.

    Nadasdi, L., Yamashiro, D., Chung, D,, Tarczy-Hornoch, K,, Adriaenssens, P, and Ramachandran, J. (1995). Structure-activity analysis of a Conus peptide blocker of N-type neuronal calcium channels. Biochemistry. 34: 8076-8081. Neurex Corporation, Menlo Park, California 94025, USA.
    Abstract: The synthetic peptide SNX-111 corresponding to the sequence of the omega-conopeptide MVIIA from the venom of the marine snail Conus magus is a highly potent and selective antagonist of N-type calcium channels. We have synthesized and characterized a large number of analogs of SNX-111 in order to elucidate the structural features of the peptide involved in blocking N-type calcium channels. Comparison of the binding of SNX-111 and its analogs to rat brain synaptosomal membranes rich in N-type channels revealed that, among the four lysines and two arginines in the molecule, lysine in position 2 and arginines at position 10 and 21 are important for the interaction of SNX-111 with N-type channels. The importance of the middle segment from residues 9 through 14 for this binding interaction was revealed by substitution of the individual residues as well as by the construction of hybrid peptides in which the residues 9-12 in SNX-111 and another conopeptide, SNX-183, corresponding to a peptide SVIB from Conus striatus, were interchanged. Introduction of the sequence SRLM from SNX-111 in place of RKTS in position 9-12 in SNX-183 resulted in a 38-fold increase in affinity. PMID: 7794920, UI: 95315196 [SNX-111, NIH 95315196]

    Nai Q, McIntosh JM, Margiotta JF.(2003) Relating neuronal nicotinic acetylcholine receptor subtypes defined by subunit composition and channel function. Mol Pharmacol. 63: 311-324.
    Department of Anatomy and Neurobiology, Medical College of Ohio, Toledo, Ohio 43614, USA.
    Abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) are widespread, diverse ion channels involved in synaptic signaling, addiction, and disease. Despite their importance, the relationship between native nAChR subunit composition and function remains poorly defined. Chick ciliary ganglion neurons express two major nAChR types: those recognized by alpha-bungarotoxin (alphaBgt), nearly all of which contain only alpha7 subunits (alpha7-nAChRs) and those insensitive to alphaBgt, which contain alpha3, alpha5, beta4, and, in some cases, beta2 subunits (alpha3*-nAChRs). We explored the relationship between nAChR composition and channel function using toxins recognizing alpha7 subunits (alphaBgt), and alpha3/beta4 (alpha-conotoxin-AuIB), or alpha3/beta2 (alpha-conotoxin-MII) subunit interfaces to perturb responses induced by nicotine, alpha7-, or alpha3-selective agonists (GTS-21 or epibatidine, respectively). Using these reagents, fast-decaying whole-cell current components were attributed solely to alpha7-nAChRs, and slow-decaying components mostly to alpha3*-nAChRs. In outside-out patches, nicotine activated brief 60- and 80-pS single nAChR channel events, and mixed-duration 25- and 40-pS nAChR events. Subsequently, 60- and 80-pS nAChR events and most brief 25- and 40-pS events were attributed to alpha7-nAChRs, and long 25- and 40-pS events to alpha3*-nAChRs. alpha3*-nAChRs lacking beta2 subunits seemed responsible for long 25 pS nAChR events, whereas those containing beta2 subunits mediated the long 40 pS nAChR events that dominate single-channel records. These results reveal greater functional heterogeneity for alpha7-nAChRs than previously expected and indicate that beta2 subunits contribute importantly to alpha3*-nAChR function. By linking structural to functional nAChR subtypes, the findings also illustrate a useful pharmacological strategy for selectively targeting nAChRs.

    Nakamura, T., Zhonghua, Y., Fainzilber, M. and Burlingame, A.L. (1996) Mass spectrometric-based revision of the structure of a cysteine-rich peptide toxin with gamma-carboxyglutamic acid, TxVIIA, from the sea snail, Conus textile. Protein Science 5: 524-530.
    [Revised structure studies on Conotoxin TxVIIA which has the conserved Cys framework of delta-conotoxins and omega-conotoxins, paralytic activity against mollusks and contains two gamma carboxyglutamic acid (Gla) residues and a high negative charge (-4). ]

    Narayana, A.K. (2005) Elan: ziconotide review focused on off-label uses. Am J Hosp Palliat Care. 22 (6): 408.
    [No abstract available. Comment on Prommer, E.E. (2005) Ziconotide: can we use it in palliative care? Am J Hosp Palliat Care. 22(5):369-374. ]

    Nielsen JS, Buczek P, Bulaj G. (2004) Cosolvent-assisted oxidative folding of a bicyclic alpha-conotoxin ImI. J Pept Sci. 10(5): 249-256.
    Cognetix, Inc., 421 Wakara Way, Suite 201, Salt Lake City, Utah 84108, USA.

    Abstract: alpha-Conotoxin ImI is a 12-amino acid peptide, found in the venom of the marine snail Conus imperialis. This conotoxin is a selective antagonist of alpha7 nicotinic acetylcholine receptors. To produce biologically active alpha-ImI, disulfide bonds must be formed between Cys2-Cys8 and Cys3-Cys12. Oxidative folding of bicyclic conotoxins, such as alpha-ImI, has been traditionally achieved using two-step oxidation protocols with orthogonal protection on two native pairs of cysteines. In this work, two alternative oxidation protocols were explored: (1) the recently described one-pot oxidation of t-butyl/4-methylbenzyl protected Cys pairs and (2) direct oxidative folding. In contrast to the first method, the latter one resulted in high yields of correctly folded alpha-ImI. The addition of organic cosolvents, such as methanol, ethanol or isopropanol into the folding mixture significantly increased the accumulation of the native peptide. This effect was also observed for another conotoxin, alpha-PnIA. It is suggested that cosolvent-assisted direct oxidation might be of general use for other bicyclic alpha-conotoxins, but efficiency should be assessed on a case-by-case basis. PMID: 15160836 [PubMed - indexed for MEDLINE]

    Nevin, S.T., Millard, E.L., Craik, D.J., Daly, N.L. and Adams, D.J. (2005) The effect of the extended N-terminal tail of alpha-conotoxin GID, on the inhibition of neuronal nicotinic acetylcholine receptors. Proc. 25th Annual Meeting, Australian Neuroscience Society. Perth, 25 January-2 February 2005, POS-MON-077

    Newcomb, R., Gaur, S., Bell, J.R., Cruz, L. (1995) Structural and biosynthetic properties of peptides in cone snail venoms. Peptides 16, 1007-

    Nimorakiotakisn B. and Winkel, K.D. (2003) Marine envenomations. Part 2 -- Other marine envenomations. Aust Fam Physician 32: 975-979.
    Epworth Hospital, Australian Venom Research Unit, Department of Pharmacology, University of Melbourne, Victoria.

    Abstract: BACKGROUND: Australian waters contain a variety of venomous creatures, including jellyfish, stinging fish, blue-ringed octopus, sea snakes, cone snails and stingrays. OBJECTIVE: Part 2 of this article focusses on common marine envenomations other than jellyfish stings. DISCUSSION: Even though mortality from these envenomations is low, there is a high level of morbidity especially with stonefish and other stinging fish envenomations. Some envenomations, however, are serious enough to require antivenom treatment and deaths still occasionally occur.

    Nishiuchi, Y. and Sakakibara, S. (1982) Primary and secondary structure of conotoxin GI, a neurotoxic tidecapeptide from a marine snail. FEBS Letters 148: 260-262.
    [Conotoxin GI, GIA and GII, stability, toxicity, mice, LD50=12ug/kg]

    Nishiuchi, Y. and Sakakibara, S. (1983) Synthesis of conotoxin MI and GII: structure-activity relationship of conotoxins. In: Peptide Chemistry 1983 (Edited by E. Munekata) Protein Research Foundation, Osaka, (1984) pp. 191-196.
    [Conotoxin MI, GI, GIA and GII. Synthesised three types of each secondary structure analog of conotoxin MI and GII to confirm which secondary structure is that of the natural toxin. Tested lethal toxicity in mice of disulfide analogs of conotoxins MI, GI and GII. Lethal toxicitieis were also compared with other analogs of conotoxin MI, all of which have the B-type or monodisulfide-type structures. Removal of the amide group reduced the toxicity to one fourth of the originial level and removal of the N-terminal Gly-Arg together with the C-terminal amide group reduced it to one-thirtieth. Opening any disulfide bond in the molecule resulted in complete loss in toxicity. Single replacement of Pro with Gly also resulted in complete loss in toxicity. Minimum structure for activity is the core part of a double cyclic structureand that the proline in the ring plasy an imprtant role in keeping the essential higher ordred structure or acting as a binding site to the receptor. Analogs tested included - MI, Des-NH4(14) MI, Des-(Gly1.Arg2)MI, Des-(Gly1.Arg2.NH2(14))MI), Cys(Acm)3,8)MI, Cys(Acm)4,14)MI, Cys(Acm)3.4.8.14)MI, (Gly6)MI, GI and GII. ]

    Newcomb, R., Gaur, S., Bell, J.R. and Cruz, L.(1995) Structural and Biosynthetic Properties of Peptides in Cone Snail VenomsPeptides, Annual 16: 1007-1018.
    Abstract: Venoms of the predatory cone snails Conus textile, Conus striatus, and Conus magus were subjected to comprehensive analysis of peptide content. With the fish-eating cone snails C. magus and C. striatus, the most abundant venom peptides were of ~ 30-50 residues, whereas the predominant peptides in the venom of the mollusc-eating snail, C. textile, were of 20-35 residues. Amino acid sequencing revealed an identical but unusual amino acid in a conserved position in four novel omega-type peptides from the C. textile venom. Two conserved amino acid sequences were obtained from the venoms of both C. magus and C. striatus. The amino acid compositions of the isolated C. textile peptides and the expected processing products of the propeptides (42) were compared. Despite the recovery in abundance of the carboxyl-terminal omega-type peptides, none of the isolated peptides had compositions expected from the propeptide amino-terminal fragments. We conclude that there are likely mechanisms for excluding the amino-terminal propeptide fragments from this venom, resulting in a venom with greater potency. Amounts of the different omega-type peptides in the venom vary widely, suggesting a distinct mechanism that results in the selective synthesis of different bioactive carboxyl-terminal propeptide fragments at elevated levels.

    Nimorakiotakis B, Winkel KD. (2003) Marine envenomations. Part 2--Other marine envenomations. Aust Fam Physician. 32 :975-979.
    Epworth Hospital, Australian Venom Research Unit, Department of Pharmacology, University of Melbourne, Victoria.
    Abstract: BACKGROUND: Australian waters contain a variety of venomous creatures, including jellyfish, stinging fish, blue-ringed octopus, sea snakes, cone snails and stingrays. OBJECTIVE: Part 2 of this article focusses on common marine envenomations other than jellyfish stings. DISCUSSION: Even though mortality from these envenomations is low, there is a high level of morbidity especially with stonefish and other stinging fish envenomations. Some envenomations, however, are serious enough to require antivenom treatment and deaths still occasionally occur.

    NO AUTHORS (1996) Venom from killer sea snails may become pain treatment. (cone snail; SNX-111) AIDS Weekly Plus, May 20, p. 20.
    Abstract: ABSTRACT.

    North, R.A. (2003) P2X3 receptors and peripheral pain mechanisms. J. Physiol. (in press)
    Abstract: ATP released from damaged or inflamed tissues can act P2X receptors expressed on primary afferent neurons. The resulting depolarisation can initiate action potentials that are interpreted centrally as pain. P2X3 subunits are found in a subset of small-diameter, primary afferent neurons, some of which are also sensitive to capsaicin. They can form homo-oligomeric channels, or they can assemble with P2X2 subunits into hetero-oligomers. Studies with antagonists selective for P2X3-containing receptors, experiments with antisense oligonucleotides to reduce P2X3 subunit levels, and behavioural testing of P2X3 knock-out mice, all suggest a role for the P2X2/3 receptor in the signalling of chronic inflammatory pain and some features of neuropathic pain. The availability of such tools and experimental approaches promises to accelerate our understanding of the other physiological roles for P2X receptors on primary afferent neurons.
    Key words: ATP • P2 purinoceptor • Pain

    Old, (1965). On the identity of Conus pastinaca. 4pp., 1pl.

    Olivera, B. (1997) E.E. Just Lecture, 1996. Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology. Molecular Biology of the Cell 8: 2101-2109

    Olivera, B.M. (2002) CONUS VENOM PEPTIDES: Reflections from the Biology of Clades and Species. Annual Review of Ecology and Systematics 33: 25-47 Department of Biology, University of Utah, Salt Lake City, Utah 84112; email: olivera@biology.utah.edu
    Abstract: The 500 cone snail species (Conus) use complex venoms to capture prey, defend against predators and deter competitors. Most biologically active venom components are small, highly structured peptides, each encoded by a separate gene. Every Conus species has its own distinct repertoire of 100-200 venom peptides, with each peptide presumably having a physiologically relevant target in prey or potential predators/competitors. There is a remarkable interspecific divergence observed in venom peptide genes, which can be rationalized because of biotic interactions that are species specific. The peptide families/subfamilies characteristic of clades of related Conus species are potentially useful clade markers and can be used to indicate common biological mechanisms characterizing that clade. By knowing both the distribution and the physiological function of venom peptides, a type of reverse ecology becomes possible; the peptides in a Conus venom are a molecular readout of the biotic interactions of a species or clade.

    Olivera, B.M., Cruz, L.J. and Yoshikami, D. (1999) Effects of Conus peptides on the behavior of mice. Current Opinion in Neurobiology, 9: 778-786..
    Abstract: When different cone snail peptides are injected into the CNS of vertebrates, they elicit diverse behaviors primarily because of their selectivity for specific receptor or ion channel subtypes. The subcellular context of the highly localized targets (i.e. the presence of other cellular elements that are functionally linked to the targets of conopeptides) is another determinant of the elicited behavior. Recent studies have advanced our understanding of the mechanisms by which four conopeptides produce different behaviors in mice.

    Olivera, B.M., Gray, W.R., Zeikus, R., McIntosh, J.M., Varga, J., Rivier, J., De Santos, V. and Cruz, L.J. (1985) Peptide neurotoxins from fish-hunting cone snails. Science, N.Y. 230: 1338-1343. [ review]

    Olivera, B.M., Hillyard, D.R., Marsh, M. and Yoshikami, D. (1995) Combinatorial peptide libraries in drug design: lessons from venomous cone snails. Trends Biotechnol 13: 422-426.[review]

    Pallaghy, P.K. and Norton, R.S. (1999) "Refined solution structure of omega-conotoxin GVIA: implications for calcium channel binding". J Pept Res 53: 343-51 [Describes a high-resolution solution structure of this member of the 'inhibitor cystine knot' protein family. The NMR data provide an improved basis for docking GVIA with models of the calcium channel. Two qualitatively different backbone conformations in the segment from Thr11 to Asn14 persisted in the restrained simulated annealing calculations. It is possible that GVIA is genuinely flexible at this segment, spending a finite time in the alternative conformation, and this may influence its interaction with the calcium channel].

    Parker, S.L., Fu, Y., McAllen, K., Luo, J., McIntosh, J.M., Lindstrom, J.M. and Sharp, B.M. (2004) Up-Regulation of Brain Nicotinic Acetylcholine Receptors in the Rat during Long-Term Self-Administration of Nicotine: Disproportionate Increase of the {alpha}6 Subunit. Mol Pharmacol. 2004 Mar;65(3):611-622.
    Department of Pharmacology, University of Tennessee College of Medicine, 874 Union Avenue, Memphis, TN 38163. bsharp@utmem.edu

    Abstract In male rats continually self-administering nicotine (approximately 1.5 mg free base/kg/day), we found a significant increase of nicotinic acetylcholine receptors (nAChRs) labeled by epibatidine (Epb) in 11 brain areas. A large increase of high-affinity Epb binding sites was apparent in the ventral tegmentum/substantia nigra, nucleus tractus solitarii, nucleus accumbens, thalamus/subthalamus, parietal cortex, hypothalamus, and amygdala. A smaller but significant up-regulation of high-affinity Epb sites was seen in the piriform cortex, hippocampus, caudate/putamen, and cerebellar cortex. The up-regulation of nAChRs, shown by immunoadsorption and Western blotting, involved alpha4, alpha6, and beta2 subunits. As a consequence of long-term self-administration of nicotine, the alpha6 immunoreactive (IR) binding of either labeled Epb or (125)I-alpha-conotoxin MII increased to a much greater extent than did alpha4 or beta2 IR binding of Epb. In addition, the beta2 IR binding of Epb was consistently enhanced to a greater extent than was alpha4. These findings may reflect a larger surface membrane retention of alpha6-containing and, to some degree, beta2-containing nAChRs compared with alpha4-containing nAChRs during long-term self-administration of nicotine.

    Partoens P., Coen E.P., Saxena V.K., Vauquelin G., De Potter W.P.(1992) Venom of conidae: pharmacological effects on vas deferens and hippocampus. - In: Recent advances in toxinology research: 2 / Gopalakrishnakone P.[edit.], e.a., Singapore, National University of Singapore. Venome and Toxin Research Group (VTRG), 1992, pp. 309-317

    Partoens, P., Wang, J.M., Coen, E.P., Vauquelin, G. and DePotter, W.P. (1996) Two polypeptide toxins with opposite effects on calcium uptake in bovine chromaffin cells: Isolation from the venom of the marine snail Conus distans. Neurochemistry International 28: (5-6): 619-624
    <
    [Abstract: Two polypeptide toxins which modulate the uptake of 45Ca2+ in bovine chromaffin cells were isolated from the venom of the marine snail Conus distans. The molecular weights were estimated by gel electrophoresis and gel filtration to be 25.5 and 24 kDa, respectively. The purified proteins were electrophoretically homogeneous. The 25.5 kDa -component caused a concentration-dependent increase of the initial rate of 45Ca2+ uptake, but it had no effect on the stimulation evoked uptake. The 23 kDa-component produced the opposite effects ; it caused a concerntration-depenent inhibition of the stimulation evoked 45Ca2+ uptake, but it did not affect the initial rate.]

    Petrauskas, L.E.(1955) A case of cone shell poisoning by “bite” in Manus Island. Papua New Guinea Med. J. 1, 67-

    Planells-Cases R., Perez-Paya E., Messeguer A., Carreno C. and Ferrer-Montiel A. (2003) Small Molecules Targeting the NMDA Receptor Complex as Drugs for Neuropathic Pain. Mini Reviews in Medicinal Chemistry 3: 749-756
    Abstract:Pain is a complex disease that usually remains poorly treated or undertreated, especially the neuropathic pain caused by injury to the peripheral or central nervous system. Antagonists of the NMDA receptor complex have emerged as potential drugs for pain management. A strong case is being raised for non-competitive or uncompetitive antagonists with low-to-moderate affinity and fast on/offset kinetics as drugs with good therapeutic profiles, because of their reduced side effects. PMID: 14529515 [PubMed - in process]

    Placzek AN, Grassi F, Papke T, Meyer EM, Papke RL. (2004) A single point mutation confers properties of the muscle-type nicotinic acetylcholine receptor to homomeric alpha7 receptors. Mol Pharmacol.66:169-177.
    Department of Pharmacology and Therapeutics, J. Hills Miller-Health Science Center, University of Florida, Gainesville, FL 32610-0267, USA.

    Abstract Although the muscle-type and homomeric alpha7-type nicotinic acetylcholine receptors (nAChRs) share many structural features and bind alpha-bungarotoxin with high affinity, several important functional and pharmacological properties distinguish these two major nAChR subtypes. We have shown previously that amino acid sequence in the second transmembrane (TM) domain of the beta subunit is critical for pharmacological distinction between muscle type and heteromeric neuronal (e.g., ganglionic) nAChRs. We tested the hypothesis that homologous substitution of amino acid sequence from the muscle beta1 subunit into the alpha7 subunit would confer specific properties of muscle-type receptors to mutant alpha7 nAChRs. In this study, we show that a single amino acid substitution at the alpha7 TM2 6' position makes both biophysical and pharmacological properties of the mutant receptors resemble those of wild-type muscle nAChR. This mutation produces significant changes in acetylcholine potency and response kinetics, eliminating the characteristic fast desensitization of alpha7 and dramatically reducing divalent ion permeability relative to wild-type alpha7. The TM2 T6'F mutation also produces a profound increase in activation by succinylcholine compared with either wild-type alpha7 or neuronal beta-subunit-containing receptors and the loss of potentiation by 5-hydroxyindole. Thus, the alpha7 TM2 T6'F mutant displays several features that are similar to the muscle nAChR, some of which are not typically thought to be regulated by the pore-lining domain of the receptor.

    Plotkin, MJ (2000) Medicine Quest: In Search of Nature's Healing Secrets ISBN: 0670869376, Number of pages: 304, Publication date: April, 2000, ISBN: 0670869376
    Excerpt at http://print.google.com/print/doc?isbn=0670869376

    Pennisi, E. (1998) "Molecular Evolution How the Genome Readies Itself for Evolution" Science 281 5380 (21 Aug 1998) 1131 - 1134.
    Abstract Genetic change, and hence the evolution of new species, is commonly thought to result from small, random mutations in individual genes, but a growing wealth of data emphasizes that that perception is wrong. Indeed, the mutations leading to evolutionary change can involve the wholesale shuffling or duplication of the genetic material, changes that can affect the expression of genes or free up duplicated genes to evolve new functions. What's more, these changes may not be totally random: Researchers have found, for example, that some parts of the genome are more likely to be duplicated or moved to another place than others, depending on the nature of their DNA sequences. They are also learning that the enzymes that copy and maintain the DNA introduce changes in some parts of the genome and not others, creating hotspots of mutation that increase the efficiency of evolution.

    Extract:
    Nonrandom mutations The changes in the ciliate genes appear to occur randomly, but researchers studying other species are finding, says Caporale, that the "rate of mutation is not monotonous throughout the whole genome." One striking example comes from Baldomero Olivera, a molecular biologist at the University of Utah, Salt Lake City, who has been assessing the incredible variation that exists in the toxins of predatory Conus snails.
    With 500 species, these organisms are the most successful marine invertebrates. All use venom-laden harpoons to immobilize worms, fish, and other mollusks for food, and depending on the species, the venom contains 50 to 200 peptides. "Each Conus has its own distinct set" of toxin peptides, says Olivera. The genetic variation responsible for this toxin diversity, which may enable Conus species to identify one another, seems to be concentrated at particular hotspots in the snail DNA.
    When Olivera and his colleagues began looking at the coding sequences for the large precursor proteins that break down to form the toxin peptides, they found that the first coding section, or exon, was almost identical in the pairs of Conus species examined. In contrast, Olivera reported at the meeting, the third exon, which is the one that codes for the peptide that becomes part of the venomous cocktail, "has just gone crazy in terms of changes." Because normally the functional parts of precursor proteins tend to change less over the course of evolution than the other parts, this finding suggests, he says, that the malleable exon somehow has a built-in tendency to mutate. The snails "are a good example of how expert nature is in using genome flexibility ... to generate genetic variation," says Thomas Kunkel, a biochemist at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
    Kunkel stresses that there could be several different explanations for such mutational hot spots. For one thing, he notes, the efficacy with which the errors that creep into the genome are repaired can vary greatly. In test tube studies of DNA repair enzymes, Kunkel finds that the error rate for the repair of mistakes made during DNA replication can vary from 99% to 3%, depending on the nature of the sequence that needs repair. That may be because the sequence influences the ease with which the repair enzymes do their job.
    What's more, some sequences are much more prone to error when the DNA is copied than others. In particular, DNA consisting of the same base repeated several times or simple two- and three-base repeats can be quite hard to replicate accurately. The problem is that the newly synthesized strand tends to slip relative to the strand being copied so that it may end up longer or shorter than the original, depending on whether it slips forward or backward.

    Price-Carter, M., Gray, W.M. and Goldenberg, D.P. (1996). Folding of omega-conotoxins: 1. Efficient disulfide-coupled folding of mature sequences in vitro. Biochemistry 35: 15537-15546.

    Price-Carter, M., Gray, W.M. and Goldenberg, D.P. (1996). Folding of omega-conotoxins: 2. Influence of precursor sequences and protein disulfide isomerase. Biochemistry 35: 15547-15557.

    Prommer, E.E. (2005) Ziconotide: can we use it in palliative care? Am J Hosp Palliat Care. 22 (5):369-374. Comment in: Am J Hosp Palliat Care. 2005 Nov-Dec;22(6):408.

    Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, California, USA.
    Abstract: Ziconotide (PRIALT) is a new nonopioid treatment for chronic pain. It is a peptide that is the synthetic analog of the omega-conotoxin, derived from the marine snail, Conus magus. The therapeutic benefit of ziconotide derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels. Interference with these channels inhibits input from pain-sensing primary nociceptors. A recent clinical trial demonstrated that ziconotide has a significant analgesic effect compared to placebo in patients considered intolerant or refractory to other treatment such as systemic analgesics, adjunctive therapies, or intrathecal (IT) morphine. Thus, ziconotide is the first of a new class of agents--N-type calcium channel blockers, or NCCBs. Ziconotide may represent another option for patients with refractory pain.
    Publication Types: Review

    Prorok, M., Warder, S.E., Blandl, T. and Castellino, F.J. (1996) Calcium-binding properties of synthetic gamma-carboxyglutamic acid-containing marine cone snail "sleeper" peptides, conantokin-G and conantokin-T. Biochemistry, 35: 16528-16535. .
    Abstract: Two Conus-derived peptides, conantokin-G (con-G), a 17-residue polypeptide with five residues of gamma-carboxyglutamic acid (Gla) and conantokin-T (con-T), a 21-residue polypeptide with four residues of Gla, were totally synthesized. Calcium binding isotherms were obtained for each peptide and were found to differ considerably from each other. Findings showed that synthetic con-G and con-T undergo large and defined conformational changes in the presence of Ca2+.

    Prorok, M., Warder, S.E., Blandl, T. and Castellino, F.J. (1997) Calcium binding properties of synthetic gamma-carboxyglutamic acid-containing marine cone snail 'sleeper' peptides, conantokin-G and conantokin-T.(Correction Notice)Biochemistry, 36: 12394..
    Abstract: Marine snails called purple cones emit potent neurotoxins through a hollow harpoon, causing instant paralysis in their prey. These same toxins show promise as chronic pain treatment, such as in cancer and AIDS. They target a calcium channel subtype in nerve cells that carry pain impulses.

    Raftos, D. and Nair, S. (2004) Tunicate cytokine-like molecules and their involvement in host defense responses. Prog Mol Subcell Biol. 2004;34:165-82. Review.
    Department of Biological Sciences, Macquarie University, North Ryde, NSW 2109, Australia.

    Abstract: Tunicates (ascidians or sea squirts) are a large group of invertebrate chordates that are closely related to vertebrates. Their critical phylogenetic position has stimulated substantial interest in their host defense ("immune") responses. Whilst this interest has generated a wealth of knowledge regarding the humoral and cellular mechanisms that undertake defensive responses, there is less known about the regulation of those reactions. This chapter focuses on three cellular responses (cell proliferation, phagocytosis and chemotaxis) that are known to be regulated by cytophilic humoral molecules. Some of the humoral factors that affect these responses have functional and physicochemical similarities to vertebrate cytokines, like interleukin-1. However, the only regulatory molecules that have been characterized at a molecular level bear far greater similarity to C-type lectins or complement components. Publication Types: Review Review, Tutorial

    Rash, L.D. and Hodgson, W.C. (2002) Pharmacology and biochemistry of spider venoms [Review] Toxicon, 40: 225-254.
    Abstract: Spider venoms represent an incredible source of biologically active substances which selectively target a variety of vital physiological functions in both insects and mammals. Many toxins isolated from spider venoms have been invaluable in helping to determine the role and diversity of neuronal ion channels and the process of exocytosis. In addition, there is enormous potential for the use of insect specific toxins from animal sources in agriculture. For these reasons, the past 15–20 years has seen a dramatic increase in studies on the venoms of many animals, particularly scorpions and spiders. This review covers the pharmacological and biochemical activities of spider venoms and the nature of the active components. In particular, it focuses on the wide variety of ion channel toxins, novel non-neurotoxic peptide toxins, enzymes and low molecular weight compounds that have been isolated. It also discusses the intraspecific sex differences in given species of spiders.

    RICHARD, 1983. 2 n.sp. of Conus from New Caledonia: C. boucheti & kanakinus. 6pp., 9figs. Euro 1.55

    Rice, R.D. and Halstead, B.W. (1968) Report of fatal cone shell sting by Conus geographus Linnaeus. Toxicon. 5: 223-224 (1968).

    Rigby, A.C., Baleja, J.D., Li, L., Pedersen, L.G., Furie, B.C. and Furie, B. (1997) Role of gamma-carboxyglutamic acid in the calcium-induced structural transition of conantokin G, a conotoxin from the marine snail Conus geographus. Biochemistry, 36: 15677-15685..
    Abstract: The function of gamma-carboxyglutamic acid (Gla) in the calcium-induced structural transition of conantokin G was examined. Conantokin G is a Gla-containing conotoxin isolated from the venom of the marine cone snail Conus geographus. The three-dimensional structure of the conantokin G/Ca2+ complex was determined and compared to the high-resolution structure of conantokin G in the absence of metal ions. Findings showed that upon binding of Ca2+ to Gla, conantokin G undergoes a conformation transition from a distorted curvilinear 3(sub 10) helix to a linear alpha-helix.
    Rigby, A.C., Lucas-Meunier, E., Kalume, D.E., Eva Czerwiec, E., Hambe, B., Dahlqvist, I., Fossier, P., Baux, G., Roepstorff,P., Baleja,J.D., Furie,B.C., Furie,B. and Stenflo, J.(1999) A conotoxin from Conus textile with unusual posttranslational modifications reduces presynaptic Ca2+ influx. PNAS(USA), 96: 5758-5764. .
    Reference reporting the identification, characterization, and structure of a gamma-carboxyglutamic acid-containing peptide, conotoxin e-TxIX, from Conus textile. This conotoxin has four cysteine residues, and an unparalleled degree of posttranslational processing including bromination, hydroxylation, and glycosylation. This conotoxin selectively reduces neurotransmitter release at  Aplysia cholinergic synapses by reducing the presynaptic influx of Ca2+ in a slow and reversible fashion.

    Abstract: Cone snails are gastropod mollusks of the genus Conus that live in tropical marine habitats. They are predators that paralyze their prey by injection of venom containing a plethora of small, conformationally constrained peptides (conotoxins). We report the identification, characterization, and structure of a [Gamma]-carboxyglutamic acid-containing peptide, conotoxin [Epsilon]-TxIX, isolated from the venom of the molluscivorous cone snail, Conus textile. The disulfide bonding pattern of the four cysteine residues, an unparalleled degree of posttranslational processing including bromination, hydroxylation, and glycosylation define a family of conotoxins that may target presynaptic [Ca2+] channels or act on G protein-coupled presynaptic receptors via another mechanism. This conotoxin selectively reduces neurotransmitter release at an Aplysia cholinergic synapse by reducing the presynaptic influx of [Ca2+] in a slow and reversible fashion. The three-dimensional structure, determined by two-dimensional 1H NMR spectroscopy, identifies an electronegative patch created by the side chains of two [Gamma]-carboxyglutamic acid residues that extend outward from a cavernous cleft. The glycosylated threonine and hydroxylated proline enclose a localized hydrophobic region centered on the brominated tryptophan residue within the constrained intercysteine region.

    RÖCKEL & al., 1990. Zur Identität von C. lizardensis & C. sibogae - mit Beschreibung 3er neuer Conus-Arten von Queensland, Australien. 29pp., 10pls. (1col.pl.), 1tab., 4figs., English summ.; combined with: RÖCKEL & al., 1990. Conus species from the W.ern Indian Ocean, dredged by Soviet biologists. 5pp., 1fig., 1tab.

    RÖCKEL, D., KORN, W. & KOHN, A.J., 1995. Manual of the Living Conidae, Vol. 1: Indo-Pacific Region. Weisbaden.

    RÖCKEL & al., 1995. Deep-water Cones from the New Caledonia region. 38pp., 1tab., 56figs. (21col.figs.), French summ., tear in last p. Euro 9.00

    ROLÁN, E. (1990). Descripcion de nuevas especies y subspecies del Genero Conus (Mollusca, Neogastropoda) para el Archipelago de Cabo Verde. Iberus, Sup. 2: 5-70.

    ROLÁN, E. (1991)"La famila Conidae (Mollusca, Gastropoda) en al Archipielago de Cabo Verde (Africa Occidental)", Dept de Zoologia, Universidad de Santiago de Compstela.

    ROLÁN, E., MONTERIRO, A. and FERNANDES, C. (1998)"Cone Shells from Cape Verde Island: New developments, with description of a new species". La Conchiglia, no. 286 (Jan-March issue) 36-44

    Rosenberg, (1998), Reproducibility of results in phylogenetic analysis of mollusks: a reanalysis of the Taylor & al. (1993) data set for conoidean gastropods. 10pp., 1tab., 7figs. Euro 1.60

    Rueter, L.E., Kohlhaas, K.L., Curzon, P., Surowy, C.S. and Meyer, M.D. (2003) Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain. Pain. 103: 269-276.
    Neurological Research, D4N5 AP9A, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA. lynne.e.rueter@abbott.com
    Abstract: Neuronal nicotinic receptor (NNR) agonists such as ABT 594 have been shown to be effective in a wide range of preclinical models of acute and neuropathic pain. The present study, using the NNR agonist A-85380, sought to determine if NNR agonists are acting via similar or differing mechanisms to induce anti-nociception and anti-allodynia. A systemic administration of the quaternary NNR antagonist chlorisondamine (0.4 micromol/kg, intraperitoneal (i.p.)) did not alter A-85380-induced (0.75 micromol/kg, i.p.) anti-nociception in the rat paw withdrawal model of acute thermal pain. In contrast, previous studies have demonstrated that blockade of central NNRs by prior administration of chlorisondamine (10 microg i.c.v.) prevents A-85380 induced anti-nociception indicating a predominantly central site of action of NNR agonists in relieving acute pain. In the rat spinal nerve ligation model of neuropathic pain, A-85380 induced a dose-dependent anti-allodynia (0.5-1.0 micromol/kg) that was blocked by pretreatment with mecamylamine (1 micromol/kg). Interestingly, unlike acute pain, both systemic and central administration of chlorisondamine blocked A-85380-induced anti-allodynia, an effect that was determined not to be due to a non-specific effect of chlorisondamine or to chlorisondamine crossing the blood-brain barrier. The peripheral site of action was shown not to be the primary receptive field, since A-85380 had equally potent anti-allodynic effects when it was injected into either the affected or unaffected paw. In contrast, infusion of A-85380 directly onto the L5 dorsal root ganglion on the affected side resulted in a dose-dependent and marked anti-allodynia (10-20 microg) at doses that had no effect when injected systemically. This effect was blocked by pretreatment with chlorisondamine. Together these data further support the idea that different mechanisms underlie different pain states and suggest that the effects of NNR agonists in neuropathic pain may be due in part to peripheral actions of the compounds.

    Ruiz, G. and Banos, J.E. (2005) The effect of endoneurial nerve growth factor on calcitonin gene-related peptide expression in primary sensory neurons. Brain Res.1042: 44-52.
    Institute of Pharmacy, Universidad Austral de Chile, Casilla 567, Valdivia, Chile; Department of Pharmacology, Therapeutics and Toxicology, School of Medicine, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain.

    Abstract:Recent findings indicate that calcitonin gene-related peptide (CGRP) is involved in neuropathic pain, this peptide being up-regulated in a small population of large- and medium-sized primary sensory neurons after peripheral nerve injury. In adult animals, the expression of CGRP is regulated by nerve growth factor (NGF). After nerve injury, NGF is up-regulated at the injury site for several weeks, and this up-regulation contributes to the onset of neuropathic pain. Using immunohistochemistry, we investigated the time course of the effect of an endoneurial injection of NGF on the expression of CGRP in primary sensory neurons. NGF increased the percentage of medium- to large-sized DRG neuron profiles expressing CGRP, did not modify the percentage of small-sized neurons expressing CGRP, and increased CGRP expression in the laminae III and IV of the dorsal horn. The effects of NGF were evident as soon as 1 day after endoneurial injection, and lasted for 5 days. Ten days after the injection of NGF, the patterns of CGRP expression in the DRG were normal, whereas a slight decrease in CGRP content was observed in the dorsal horn. The injection of vehicle did not produce any change on CGRP expression in primary sensory neurons. These results suggest that endoneurial NGF is responsible for the increase in CGRP expression in some large-sized neurons and their central processes observed after nerve injury in animal models of neuropathic pain. Our findings contribute to the understanding of the role of NGF in neuropathic pain.

    Salminen, O., Murphy, K.L., McIntosh, J.M., Drago, J., Marks, M.J., Collins, A.C., Grady, S.R. (2004) Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice. Mol Pharmacol. 65:1526-1535.
    Abstract: Pharmacological evaluation of nicotine-stimulated dopamine release from striatum has yielded data consistent with activation of a single population of nicotinic acetylcholine receptors (nAChR). However, discovery that alpha-conotoxin MII (alpha-CtxMII) partially inhibits the response indicates that two classes of presynaptic nAChRs mediate dopamine release. We have investigated the pharmacology and subunit composition of these two classes of nAChR. Inhibition of nicotine-stimulated dopamine release from mouse striatal synaptosomes by alpha-CtxMII occurs within minutes; recovery is slow. The IC(50) is 1 to 3 nM. alpha-CtxMII-sensitive and -resistant components have significant differences in pharmacology. The five agonists tested were more potent at activating the alpha-CtxMII-sensitive nAChRs; indeed, this receptor is the highest affinity functional nAChR found, so far, in mouse brain. In addition, cytisine was more efficacious at the alpha-CtxMII-sensitive sites. Methyllycaconitine was 9-fold more potent at inhibiting the alpha-CtxMII-sensitive sites, whereas dihydro-beta-erythroidine was a 7-fold more potent inhibitor of the alpha-CtxMII-resistant response. Both the transient and persistent phases of nicotine-stimulated dopamine release were partially inhibited by alpha-CtxMII with equal potency. The subunit composition of functional nAChRs, was assessed in mice with null mutations for individual nAChR subunits. The beta2 subunit is an absolute requirement for both classes. In contrast, deletion of beta4 or alpha7 subunits had no effect. The alpha-CtxMII-sensitive response requires beta3 and is partially dependent upon alpha4 subunits, probably alpha6beta3beta2 and alpha4alpha6beta3beta2, whereas the alpha-CtxMII-resistant release requires alpha4 and is partially dependent upon alpha5 subunits, probably alpha4beta2 and alpha4alpha5beta2.

    Salminen, O., Whiteaker, P., Grady, S.R., Collins, A.C., McIntosh, J.M. and Marks, M.J. (2005) The subunit composition and pharmacology of alpha-Conotoxin MII-binding nicotinic acetylcholine receptors studied by a novel membrane-binding assay. Neuropharmacology. 48:696-705.
    Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.

    Abstract: The subunit composition and pharmacology of alpha-Conotoxin MII-binding (alpha-CtxMII) nicotinic acetylcholine receptors (nAChR) was studied by an improved [(125)I]-alpha-CtxMII membrane binding method. This binding method facilitates pharmacological studies that have been difficult to accomplish with [(125)I]-alpha-CtxMII autoradiography or alpha-CtxMII inhibition of [(125)I]-epibatidine binding. Binding densities and K(d)-values obtained by this [(125)I]-alpha-CtxMII membrane binding were similar to the values obtained by autoradiography or alpha-CtxMII inhibition of [(125)I]-epibatidine binding, verifying that each of these approaches measures the same nAChR population. Binding results with nAChR subunit-null mutant mice confirm and extend observations from earlier studies: [(125)I]-alpha-CtxMII binding measures two sets of alpha6beta2* nAChR (alpha4alpha6beta2beta3 or alpha6beta2beta3). Most nicotinic agonists and antagonists show monophasic inhibition of [(125)I]-alpha-CtxMII binding, indicating that alpha4alpha6beta2beta3 and alpha6beta2beta3 have similar binding properties. Comparison of the binding and activation profiles of alpha6beta2* nAChR to those of other nAChR subtypes (alpha4beta2* and beta4*) indicates that these receptors have distinctly different pharmacology indicating that it may be possible to target alpha6beta2* nAChR selectively to develop compounds that might be therapeutically useful.

    Saminathan R, Babuji S, Sethupathy S, Viswanathan P, Balasubramanian T and Gopalakrishanakone P.(2006) Clinico-toxinological characterization of the acute effects of the venom of the marine snail, Conus loroisii. Acta Trop. 97(1):75-87.

    Sandall, D.W., Satkunanathan, N., Keays, D.A., Polidano, M.A., Liping, X., Pham, V., Down, J.G., Khalil, Z., Livett, B.G. and Gayler, K.R. (2003) "A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo". Biochemistry 42 (22) 6904-6911.
    Abstract: We describe the identification of a conopeptide sequence in venom duct mRNA from Conus victoriae that suppresses a vascular response to pain in the rat. PCR-RACE was used to screen venom duct cDNAs for those transcripts that encode specific antagonists of vertebrate neuronal nicotinic acetylcholine receptors (nAChRs). One of these peptides, Vc1.1, was active as an antagonist of neuronal nAChRs in receptor binding and functional studies in bovine chromaffin cells. It also suppressed the vascular responses to unmyelinated sensory nerve C-fiber activation in rats. Such vascular responses are involved in pain transmission. Furthermore, its ability to suppress C-fiber function was greater than that of MVIIA, an omega-conotoxin with known analgesic activity in rats and humans. Vc1.1 has a high degree of sequence similarity to the alpha-conotoxin family of peptides and has the 4,7 loop structure characteristic of the subfamily of peptides that act on neuronal-type nAChRs. The results suggest that neuronal alpha-conotoxins should be further investigated with respect to their potential to suppress pain.

    Sarasua, 1977. 2 Nuevas Formas Cubanas del Género Conus. 4pp., 1pl., English summ. Euro 0.85

    Savarin, P., Guenneugues, M., Gilquin, B., Lamthanh, H., Gasparini, S., Zinn-Justin, S. and Menez, A. (1998) Three-dimensional structure of kappa-conotoxin PVIIA, a novel potassium channel-blocking toxin from cone snails. Biochemistry, 37: 5407-5417..
    Abstract: A study was conducted to describe the structure of kappa-conotoxin from the venom of Conus purpurascens responsible for potassium channel blockage. The chemical synthesis of the cone snail toxin, kappa-conotoxin PVIIA, exhibited similarity with omega- and delta conotoxins. Using the nuclear magnetic resonance spectroscopy, the three-dimensional structure of the cone snail's toxin showed two large parallel loops which were stabilized by a triple-stranded antiparallel beta-sheet and three disulfide bridges.

    Saxena V.K., Partoens P., De Block J., Coen E.P., Vauquelin G., De Potter W.P. (1992). Inhibition of evoked neurotransmitter release from rat hippocampus by a polypeptide toxin isolated from the marine snail Conus distans. Neurochemistry International, 20: 69-74

    Shon, K.-J., Stocker, M., Terlau, H., Stühmer, W., Jacobson, R., Walker, C., Grilley, M., Marsh, M., Hillyard, D., Gray, W.R. and Olivera, B.M.(1998) k-conotoxin PVIIa: A peptide inhibiting the Shaker K+ channel. J. Biological Chemistry, 273, 33 - 38.

    Schultz M.C. (1983) A correlated light and electron microscopic study of the structure and secretory activity of the accessory salivary glands of the marine gastropods, Conus flavidus and C. vexillum (neogastropoda, conacea). J Morphol.176: 89-111.
    Abstract: The structure and secretory activity of the accessory salivary gland in two species of Conus were examined using routine and histochemical techniques of light, scanning and transmission electron microscopy. The composite layers of the accessory salivary gland of Conus are a luminal epithelium, fibromuscular layer, submuscular layer, and a capsule. In Conus flavidus and C. vexillum , the luminal epithelium is formed by epitheliocytes and cytoplasmic processes extending from the secretory cells, whose perikarya form the submuscular layer. The processes carry secretory cell products (chiefly Golgi-derived glycoprotein) across the fibromuscular layer and terminate between epitheliocytes (at the bases of the secretory canaliculi) or beyond the surface of the epithelial cells. Conus vexillum is distinguished from Conus flavidus by its high content of lipofuscin. Epitheliocytes are the only microvillated cells in the accessory salivary gland of Conus. Conus flavidus , epitheliocytes extrude secretory granules, various types of cytoplasmic blebs and clear vesicles by apocrine "pinching off." Clear vesicles are shed from the tips of microvilli. The luminal epithelial cells of C. vexillum similarly egest clear vesicles, but normally undergo additional holocrine secretion to release lipofuscin. The secretions of epitheliocytes appear to be major products of the accessory salivary gland: consideration of secretory activities by both epitheliocytes and secretory cells will therefore be necessary when directly investigating accessory salivary gland function in Conus.

    Servent, D., Thanh, H.L., Antil, S., Bertrand,D., Corringer, P.-J., Changeux, J.-P. and Menez, A. (1998) Functional determinants by which snake and cone snail toxins block the alpha7 neuronal nicotinic acetylcholine receptors. J. Physiol. Paris, 92: 107-112. .
    Abstract: Snakes and cone snails produce toxins which block muscular and/or neuronal nicotinic acetylcholine receptors (AChRs). This paper mostly focuses on the determinants by which a snake long chain curaremimetic toxin and the cone snail toxin ImI bind specifically to the alpha7 neuronal receptor. In both cases, the site involves a small turn-like structure constrained by two half-cystines.

    SEVERAL AUTHORS, 1935.Résultats Scientifiques du Voyage aus Indes Orientales Néerlandaises de LL. AA. RR. le Prince & la Princesse Léopold de Belgique; containing: DAUTZENBERG, 1935. 2(17). Gastéropodes marins. 1. Familie Terebridae.&: DAUTZENBERG, 1935. 2(18). Gastéropodes marins. 3. Familie Conidae. 282pp., 3col.pls.

    Severance EG, Zhang H, Cruz Y, Pakhlevaniants S, Hadley SH, Amin J, Wecker L, Reed C, Cuevas J. (2004) The {alpha}7 Nicotinic Acetylcholine Receptor Subunit Exists in Two Isoforms that Contribute to Functional Ligand-Gated Ion Channels. Mol Pharmacol. 2004 Sep;66(3):420-429.
    Department of Pharmacology and Therapeutics, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, MDC 9, Tampa, FL 33612-4799. jcuevas@hsc.usf.edu

    Abstract: Fast synaptic transmission in mammalian autonomic ganglia is mediated primarily by nicotinic receptors, and one of the most abundant nicotinic acetylcholine receptor subtypes in these neurons contains the alpha7 subunit (alpha7-nAChRs). Unlike alpha7-nAChRs expressed in other cells, the predominant alpha7-nAChR subtype found in rat intracardiac and superior cervical ganglion neurons exhibits a slow rate of desensitization and is reversibly blocked by alpha-bungarotoxin (alphaBgt). We report here the identification of an alpha7 subunit sequence variant in rat autonomic neurons that incorporates a novel 87-base pair cassette exon in the N terminus of the receptor and preserves the reading frame of the transcript. This alpha7 isoform was detected using reverse transcriptase-polymerase chain reaction techniques in neonatal rat brain and intracardiac and superior cervical ganglion neurons. Immunoblot experiments using a polyclonal antibody directed against the deduced amino acid sequence of the alpha7-2 insert showed a pattern of expression consistent with alpha7-2 subunit mRNA distribution. Moreover, the alpha7-2 subunit could be immunodepleted from protein extracts by solid-phase immunoprecipitation techniques using the anti-alpha7 monoclonal antibody 319. The alpha7-2 subunit was shown to form functional homomeric ion channels that were activated by acetylcholine and blocked by alpha-bungarotoxin when expressed in Xenopus laevis oocytes. This alpha7 isoform exhibited a slow rate of desensitization, and inhibition of these channels by alphaBgt reversed rapidly after washout. Taken together, these data indicate that the alpha7-2 subunit is capable of forming functional alphaBgt-sensitive acetylcholine receptors that resemble the alpha7-nAChRs previously identified in rat autonomic neurons. Furthermore, the distribution of the alpha7-2 isoform is not limited to peripheral neurons.

    Sine SM., Kreienkamp HJ., Bren N., Maeda R., Taylor P (1995) Molecular dissection of subunit interfaces in the acetylcholine receptor: identification of determinants of alpha-conotoxin M1 selectivity.Neuron, 15: 205-211

    [Abstract: The acetylcholine receptor from vertebrate skeletal muscle is a pentamer of homologous subunits with composition alpha 2 beta gamma delta. Its two ligand binding sites, formed at alpha-gamma and alpha-delta interfaces, differ in their affinities for agonists and competitive antagonists, owing to different contributions of the gamma and delta subunits. To identify portions of the gamma and delta subunits that contribute to the binding sites, the experiments described here use gamma-delta subunit chimeras and site-specific mutants to determine the basis of the 10,000-fold selectivity of conotoxin M1 for the sites. Three distinct regions of the extracellular domain were found to contribute to conotoxin M1 selectivity, each containing a single residue responsible for the contribution of that region. Residues K34, S111, and F172 of the gamma subunit confer low affinity to the alpha-gamma binding site, whereas the corresponding residues of the delta subunit, S36, Y113, and I178, confer high affinity to the alpha-delta site. Identification of three separate determinants of ligand selectivity suggests a limited model of the folding pattern of the extracellular domain of the subunits].

    Shon, K-J., Grilley, M., Jacobsen, R., Cartier, E., Hopkins, C., Gray, W.R., Watkins, M., Hillyard, D.R., Rivier, J., Torres, J., Yoshikami, D. and Olivera, B.M. (1997) A noncompetitive peptide inhibitor of the nicotinic acetylcholine receptor from Conus purpurascens venom. Biochemistry 36: 9581-9587.

    [Abstract: A paralytic peptide, y-conotoxin PIIIE has been purified from Conus purpurascens venom. Electrophysiological studies indicated that the peptide inhibits the nicotinic acetylcholine receptor (nAChR). However, the peptide does not block the binding of a-bungarotoxin, a competitive nAChR antagonist. Thus, y -conotoxin PIIIE appears to inbibit the receptor at a site other than the acetylcholine-binding site. As ascertained by sequence analysis, mass spectrometry and chemical synthesis, the peptide has the following covalent structure: HOOCCLYGKCRRYOGCSSASCCQR* (O=4-trans hydroxyproline; *indicates an amidated C-terminus). The disulfide connectivity of the toxin is unrelated to the a- or aA-conotoxins, the Conus peptide families that are competitive inhibitors of the nAChR, but shows homology to the m-conotoxins (which are Na+ channel blockers).]
     
    Shon KJ., Grilley MM., Marsh M., Yoshikami D., Hall AR., Kurz B., Gray WR., Imperial JS., Hillyard DR. and Olivera BM (1995) Purification, characterization, synthesis, and cloning of the lockjaw peptide from Conus purpurascens venom. Biochemistry, 34: 4913-4918
    [Abstract : The major groups of Conus peptides previously characterized from fish-hunting cone snail venoms (the alpha-, mu-, and omega-conotoxins) all blocked neuromuscular transmission. A novel activity, the "lockjaw peptide", from the fish-hunting Conus purpurascens, caused a rigid (instead of flaccid) paralysis in fish and increased excitability at the neuromuscular junction (instead of a block). We report the purification, biological activity, biochemical and preliminary physiological characterization, and chemical synthesis of the lockjaw peptide and the sequence of a cDNA clone encoding its precursor. Taken together, the data lead us to conclude that the lockjaw peptide is a vertebrate-specific delta-conotoxin, which targets voltage-sensitive sodium channels. The sequence of the peptide, which we designate delta-conotoxin PVIA, is (O = 4-trans-hydroxyproline) EACYAOGTFCGIKOGLCCSEFCLPGVCFG-NH2. This is the first of a diverse spectrum of Conus peptides which are excitotoxins in vertebrate systems].

    Shon, K., Olivera, B.M., Watkins, M., Jacobsen, R.B., Gray, W.R, Floresca, C.Z., Cruz, L.J., Hillyard, D.R., Brink, A., Terlau, H., Yoshikami, D. (1998) m -CTX PIIIA, a new peptide for discriminating among tetrodotoxin-sensitive Na channel subtypes. J. Neurosci 18: 4473-4481.

    Sharpe, I.A., Gehrmann, J., Loughnan, M.L., Thomas, L., Adams, D.A., Atkins, A., Palant, E., Craik, D.J., Adams, D.J., Alewood, P.F. and Lewis, R.J. (2001) "Two new classes of conopeptides inhibit the alpha-1-adrenoceptor and noradrenaline transporter". Nature Neurosci. 4: 902-907.
    Abstract: Cone snails use venom containing a cocktail of peptides ('conopeptides') to capture their prey. Many of these peptides also target mammalian receptors, often with exquisite selectivity. Here we report the discovery of two new classes of conopeptides. One class targets alpha 1-adrenoceptors (rho-TIA from the fish-hunting Conus tulipa), and the second class targets the neuronal noradrenaline transporter (chi-MrIA and chi-MrIB from the mollusk-hunting C. marmoreus). rho-TIA and chi-MrIA selectively modulate these important membrane-bound proteins. Both peptides act as reversible non-competitive inhibitors and provide alternative avenues for the identification of inhibitor drugs.
     
    Schroeder, J. (2001) Characterization of Hypervariability in Conotoxins. Biochemistry 218 Final Project, Autumn 2001. Stanford University, CA.
     

    Slavkin HC. (2003) Applications of pharmacogenomics in general dental practice. Pharmacogenomics. 4: 163-170. Review.
    Abstract: The human oral cavity represents a complex ecology of approximately 500 microbial species existing as commensals, and interacting with human/host factors. Perturbation of this ecosystem can lead to diseases of the oral cavity. The oral cavity also acts as a mirror of complex systemic diseases. Unique challenges and opportunities in oral healthcare exist in the diagnosis and treatment of primary disorders of the oral cavity or manifestations of systemic diseases. The completion of human and microbial genome projects has provided a wealth of information that will permit the application of pharmacogenomics - how genetic variations within the commensal and the host will impact the efficacy of drugs, and the diagnosis and treatment of oral disease. This review highlights opportunities focusing on oral health where pharmacogenomics can be applied.
     

    Smith MT, Cabot PJ, Ross FB, Robertson AD, Lewis RJ. (2000) Pain. 96:119-127.
    School of Pharmacy, The University of Queensland, St Lucia, Queensland, Brisbane, Australia.
    m.smith@pharmacy.uq.edu.au
    Abstract: The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. N-type calcium channels modulate the release of key pro-nociceptive neurotransmitters such as glutamate and substance P (SP) in the central nervous system. Considerable research interest has focused on the therapeutic potential of the peptidic omega-conopeptides, GVIA and MVIIA as novel analgesic agents, due to their potent inhibition of N-type calcium channels. Recently, the novel peptidic N-type calcium channel blocker, AM336, was isolated from the venom of the cone snail, Conus catus. Thus, the aims of this study were to (i) document the antinociceptive effects of AM336 (also known as CVID) relative to MVIIA following intrathecal (i.t.) bolus dosing in rats with adjuvant-induced chronic inflammatory pain of the right hindpaw and to (ii) quantify the inhibitory effects of AM336 relative to MVIIA on K+-evoked SP release from slices of rat spinal cord. Both AM336 and MVIIA inhibited the K+-evoked release of the pro-nociceptive neurotransmitter, SP, from rat spinal cord slices in a concentration-dependent manner (EC50 values=21.1 and 62.9 nM, respectively), consistent with the antinociceptive actions of omega-conopeptides. Following acute i.t. dosing, AM336 evoked dose-dependent antinociception (ED50 approximately 0.110 nmol) but the doses required to produce side-effects were an order of magnitude larger than the doses required to produce antinociception. For i.t. doses of MVIIA0.07 nmol, produced a dose-dependent decrease in antinociception but the incidence and severity of the side-effects continued to increase for all doses of MVIIA investigated, suggesting that dose-titration with MVIIA in the clinical setting, may be difficult.

    Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, Fisher R, Bryce DA, Mangieri EA, Luther RR, Mayo M, McGuire D, Ellis D. (2004) Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 291: 63-70.

    Division of Pain Medicine, Johns Hopkins University School of Medicine, Baltimore, Md 21205, USA. pstaats@jhmi.edu

    Abstract:CONTEXT: Ziconotide (formerly SNX-111) selectively blocks N-type voltage-sensitive calcium channels and may be effective in patients with pain that is refractory to opioid therapy or those with intolerable opioid-related adverse effects. OBJECTIVE: To assess the safety and efficacy of intrathecal ziconotide in patients with pain that is refractory to conventional treatment. DESIGN, SETTING, AND PATIENTS: Double-blind, placebo-controlled, randomized trial conducted from March 12, 1996, to July 11, 1998, at 32 study centers in the United States, Australia, and the Netherlands. Patients were 111 individuals ages 24 to 85 years with cancer or AIDS and a mean Visual Analog Scale of Pain Intensity (VASPI) score of 50 mm or greater. Patients were randomly assigned in a 2:1 ratio to receive ziconotide or placebo treatment. INTERVENTIONS: Intrathecal ziconotide was titrated over 5 to 6 days, followed by a 5-day maintenance phase for responders and crossover of nonresponders to the opposite treatment group. MAIN OUTCOME MEASURE: Mean percentage change in VASPI score from baseline to the end of the initial titration period. RESULTS: Of the evaluable population, 67 (98.5%) of 68 patients receiving ziconotide and 38 (95%) of 40 patients receiving placebo were taking opioids at baseline (median morphine equivalent dosage of 300 mg/d for the ziconotide group and 600 mg/d for the placebo group; P =.63, based on mean values), and 36 had used intrathecal morphine. Mean (SD) VASPI scores were 73.6 (1.8) mm in the ziconotide group and 77.9 (2.3) mm in the placebo group (P =.18). Mean VASPI scores improved 53.1% (95% confidence interval [CI], 44.0%-62.2%) in the ziconotide group and 18.1% (95% CI, 4.8%-31.4%) in the placebo group (P<.001), with no loss of efficacy of ziconotide in the maintenance phase. Pain relief was moderate to complete in 52.9% of patients in the ziconotide group compared with 17.5% in the placebo group (P<.001). Five patients receiving ziconotide achieved complete pain relief, and 50.0% of patients receiving ziconotide responded to therapy compared with 17.5% of those receiving placebo (P =.001). CONCLUSION: Intrathecal ziconotide provided clinically and statistically significant analgesia in patients with pain from cancer or AIDS.

    Spence, I., Gillessen, D., Gregson, R.P., Quinn, R.J. (1977) Characterization of the neurotoxic constituents of Conus geographus (L) venom. Life Sci. 21: 1759-1769.

    Spira, M.E., Hasson, A., Fainzilber, M., Gordon, D., Zlotkin, E. (1993). Chemical and electrophysiological characterization of new peptide neurotoxins from the venom of the molluscivorous snail Conus textile neovicarius: A review. Israel Journal of Medical Sciences 29 9 1993 0021-2180 530- 543.
     

    Sutherland, S.K(1983).: Australian Animal Toxins: The Creatures, their Toxins and the Care of the Poisoned Patient. Melbourne. Oxford University Press. p 396 (venomous cone shells) and p 457 (fish poisoning to eat) (1983)

    Dorene Taqi, Ian Gunyea, PA-C, Bhadresh Bhakta, MD, Venkatesh Movva, MD, Sameh Ward,MD, Mike Jenson, PA-C, CPP, Mike Royal, MD (2002) Intrathecal Ziconotide Effect on neuropathic symptoms and potential for adjunctive use with opiates: A retrospective review in 25 patients. Pain Medicine 3 (2), 180-181.
    Abstract: An ongoing, open-label, multicenter clinical trial to assess the long-term safety and tolerability of intrathecally (IT) administered ziconotide to patients with chronic, severe pain was initiated in November, 1998. As part of this study, we evaluated 52 patients with chronic intractable pain on IT ziconotide. Ziconotide is an N-type, voltage-sensitive calcium channel blocker with proven efficacy as an IT analgesic. In this trial, IT ziconotide was initiated at a dose of 0.1mcg/hr, followed by long-term ziconotide infusion with titrations as needed within study parameters. Efficacy was assessed using a visual analog scale. Of our 52 patients, 25 had primarily neuropathic pain symptoms and were on ziconotide for at least 3 months. Following the change in IT therapy, 25 patients were queried during the course of their treatment with ziconotide as to its effect on their neuropathic symptoms (dysesthesia, allodynia, paresthesia, radiculopathic symptoms etc.) and queried after discontinuing ziconotide, which was primarily due to adverse events from uptitration to cover any nociceptive pain component, on the relative effectiveness of their current IT opiate to IT ziconotide on their neuropathic symptoms and on their willingness to go back on lower dose ziconotide with their present IT opiate in an attempt to more effectively manage neuropathic symptoms. Most of the patients (18/25) observed that the neuropathic symptoms improved at lower doses of ziconotide, but when uptitration of dose was done to cover more of their pain, side effects occurred causing eventual discontinuation. These patients also observed that their IT opiate was less effective on these same neuropathic symptoms. Twenty-one of the 25 patients (84%) said they would like to try ziconotide with their opiate and 18 (72%) of them were quite sure that their neuropathic symptoms improved dramatically with the ziconotide at a dose much lower than their termination dose. Studies of low dose IT ziconotide with morphine (and other opiates) are needed to determine if the risk-benefit of ziconotide-based treatment can be enhanced with IT drug combinations.

    Taylor, J., Kantor, Y., and Sysoev, A., (1993). Foregut anatomy, feeding mechanisms, relationships and reclassification of the Conoidea (= Toxoglossa) (Gastropoda). Bulletin of the Natural History Museum, London 59, 125-170
     

    TAYLOR, 1881. Life histories of British Helices. 18pp., 1pl. [also figured: Conus brazieri].

    Terlau, H., Shon, K-J., Grilley, M., Stocker, M., Stuhmer, W. and Olivera, B.M. (1996) Strategy for rapid immobilization of prey by a fish-hunting marine snail. Nature 381: 148-151.
    [Conus purpurascens, alphaA-conotoxin, mu-conotoxin PIIIA, k-conotoxin PVIIA and delta-conotoxin PVIA. ( C.purpurascens venom contains at least three paralytic toxins, which act by blocking neuromuscular transmission; two of these, alphaA-conotoxin PIVA, which targets the nicotinic acetylcholine receptor, and mu-conotoxin PIIIA, which blocks skeletal muscle sodium channels, are not responsible for the rigid immobilization characteristic of excitotoxic shock and sudden tetanus of prey (STOP) syndrome which is brought about by a newly characterized peptide, 'fin-popping peptide' (k-conotoxin PVIIA), which inbibits the Shaker potassium channel, and the 29 amino-acid 'lock-jaw peptide' (delta-conotoxin PVIA) which delays sodium channel inactivation. Amino-acid sequence determination of k-conotoxin PVIIA shows it to be a 27 amino-acid peptide with the sequence : CRIONQKCFQHLDDCCSRKCNRFNKCV, where 'O' represents 4-trans-hydroxyproline. This 'fin-popping' peptide is the first member of a putative k-conotoxin family of K+ channel-targetted peptides. The authors have named it k-conotoxin PVIIA (k-PVIIA). At 1uM it had no effect on type II Na+ channels or the K+ channels Kv1.1 or Kv1.4 from rat brain (unpublished data).
    Summary: When C.purpurascens stings fish, STOP is elicited by two excitotoxins, one increasing Na+ influx, the other decreasing K+ efflux, leading to powerful depolarization of cells. The AChR receptor inhibitor (alphaA-conotoxin PIVA) and the voltage gated Na+ channel inhibitor (mu-conotoxin PIIIA) cause neuromuscular block and flaccid paralysis, which occur SLOWLY owing to the dispersal time to synapses, however, k-PVIIA and delta-PVIA cause RAPID excitotoxic shock to immobilize prey quickly. The immobilization of prey by C.purpurascens resembles that by sea anemones (that initially contact their prey with a single tentacle) which have convergently evolved Na+ and K+ channel-targeted excitotoxins analagous to those used by C.purpurascens].

    Terlau, H., Shon, K.-J., Grilley, M., Stocker, M., Stühmer, W. and Olivera, B.M. (1996) Strategy for rapid immobilization of prey by a fish-hunting marine snail. Nature, 381, 148 - 151.

    Texido, L., Ros, E., Martin-Satue, M., Lopez, S., Aleu, J., Marsal, J. and Solsona, C. (2005) Effect of galantamine on the human alpha7 neuronal nicotinic acetylcholine receptor, the Torpedo nicotinic acetylcholine receptor and spontaneous cholinergic synaptic activity. Br J Pharmacol. 2005 Apr 18; [Epub ahead of print]
    Laboratory of Molecular and Cellular Neurobiology, Department of Cell Biology and Pathology, Medical School-Bellvitge Campus, IDIBELL-Universitat de Barcelona, Feixa Llarga s/n, L'Hospitalet de Llobregat, E-08907, Spain.

    Abstract: Various types of anticholinesterasic agents have been used to improve the daily activities of Alzheimer's disease patients. It was recently demonstrated that Galantamine, described as a molecule with anticholinesterasic properties, is also an allosteric enhancer of human alpha4beta2 neuronal nicotinic receptor activity. We explored its effect on the human alpha7 neuronal nicotinic acetylcholine receptor (nAChR) expressed in Xenopus oocytes.Galantamine, at a concentration of 0.1 muM, increased the amplitude of acetylcholine (ACh)-induced ion currents in the human alpha7 nAChR expressed in Xenopus oocytes, but caused inhibition at higher concentrations. The maximum effect of galantamine, an increase of 22% in the amplitude of ACh-induced currents, was observed at a concentration of 250 muM Ach.The same enhancing effect was obtained in oocytes transplanted with Torpedo nicotinic acetylcholine receptor (AChR) isolated from the electric organ, but in this case the optimal concentration of galantamine was 1 muM. In this case, the maximum effect of galantamine, an increase of 35% in the amplitude of ACh-induced currents, occurred at a concentration of 50 muM ACh.Galantamine affects not only the activity of post-synaptic receptors but also the activity of nerve terminals. At a concentration of 1 muM, quantal spontaneous events, recorded in a cholinergic synapse, increased their amplitude, an effect which was independent of the anticholinesterasic activity associated with this compound. The anticholinesterasic effect was recorded in preparations treated with a galantamine concentration of 10 muM.In conclusion, our results show that galantamine enhances human alpha7 neuronal nicotinic ACh receptor activity. It also enhances muscular AChRs and the size of spontaneous cholinergic synaptic events. However, only a very narrow range of galantamine concentrations can be used for enhancing effects.British Journal of Pharmacology advance online publication, 18 April 2005; doi:10.1038/sj.bjp.0706221.

    L S Tisa, B M Olivera, and J Adler (1993) Inhibition of Escherichia coli chemotaxis by omega-conotoxin, a calcium ion channel blocker. J Bacteriol. 175: 1235–1238

    TRACEY, 1996. Mollusca of the Selsey Formation (Middle Eocene): Conoidea, Turrinae. 34pp., 7pls., 5figs., signed by author.

    Eiji Tsuchida and Taji Kurozumi (1994) Conid gastropods collected off Miyake-Shima Island, Izu-Shichito Islands by R/v Tansei-Maru (Gastropoda: Conidae) by Category : Conidae Mollusca Shells Malacology. , secondhand, 7p. 1 b/w plate, 1 map. text in Japanese, English summary and captions.

    TRYON, 1884. Manual of conchology; Structural & Systematic. - with illustrations of the species. - vol. 6. Conidć. 150pp., 31pls.,

    Tsuneki H, You Y, Toyooka N, Sasaoka T, Nemoto H, Dani JA, Kimura I.(2005) Marine alkaloids (-)-pictamine and (-)-lepadin B block neuronal nicotinic acetylcholine receptors. Biol Pharm Bull. 28 :611-614
    . Department of Clinical Pharmacology, Toyama Medical and Pharmaceutical University, Japan. htsuneki@ms.toyama-mpu.ac.jp

    Ascidians (sea squirts) contain a wealth of alkaloids, but their influence over neuronal nicotinic acetylcholine receptors (nAChRs) has not been evaluated. In this study, we examined the effects of two synthetic compounds, (-)-pictamine, a quinolizidine alkaloid from Clavelina picta, and (-)-lepadin B, a decahydroquinoline alkaloid from Clavelina lepadiformis, on major types of neuronal nicotinic receptors (alpha4beta2 and alpha7) expressed in Xenopus oocytes. We found that these alkaloids are potent blockers at these receptors: acetylcholine-elicited currents through alpha4beta2 and alpha7 receptors were blocked by (-)-pictamine with IC(50) values of 1.5 microM and 1.3 microM, respectively, and by (-)-lepadin B with IC(50) values of 0.9 microM and 0.7 microM, respectively. Interestingly, no recovery was observed after the removal of (-)-pictamine in oocytes expressing alpha4beta2 receptors, whereas the inhibited alpha7 currents quickly recovered after the removal of (-)-pictamine. Since there are few compounds that elicit irreversible blocks of alpha4beta2 receptors, (-)-pictamine will be a novel, valuable tool to remove the alpha4beta2-nAChR action from neuronal activities mediated by these two major types of nAChRs.

    Urban,M.O., Ren,K., Sablad,M. and Park, K.T. (2005) Medullary N-type and P/Q-type calcium channels contribute to neuropathy-induced allodynia. Neuroreport, 16: 563-566.
    Department of Pharmacology, Merck Research Laboratories, San Diego, CA 92121, USA.

    Abstract:The present study was designed to determine the contribution of N-type, P/Q-type and L-type calcium channels in the rostral ventromedial medulla to tactile allodynia following peripheral nerve injury. L5/L6 spinal nerve ligation in rats produced tactile allodynia, which was dose-dependently inhibited by intrarostral ventromedial medulla microinjection of the N-type calcium channel antagonist omega-conotoxin MVIIA. Similarly, intrarostral ventromedial medulla microinjection of the P/Q-type calcium channel antagonist omega-agatoxin IVA inhibited spinal nerve ligation-induced tactile allodynia, whereas intrarostral ventromedial medulla microinjection of the L-type calcium channel antagonist nimodipine had no effect. These results demonstrate that N-type and P/Q-type calcium channels in the rostral ventromedial medulla contribute to tactile allodynia following peripheral neuropathy, likely via neurotransmitter-mediated activation of descending facilitatory systems from the rostral ventromedial medulla.

    Villarroya, M., De-la Fuente, M-T., Lopez, M.G., Gandia, L. and Garcia, A.G. (1997) Distinct effects of w-toxins and various groups of Ca2+ entry inhibitors on nicotinic acetylcholine receptor and Ca2+ channels of chromaffin cells. Europ. J. Pharmacol. 320: 249-257.

    Vincler, M. and Eisenach, J.C. (2004) Plasticity of spinal nicotinic acetylcholine receptors following spinal nerve ligation. Neurosci Res. 48:139-45.

    Abstract:The nicotinic cholinergic system is known to be important in the processing of nociceptive information. In the spinal cord, nicotinic receptors are expressed on primary afferent terminals, inhibitory interneurons and descending noradrenergic and serotoninergic fibers. Following peripheral nerve injury, the expression of numerous receptors involved in nociceptive processing is altered in the superficial dorsal horn of the spinal cord. However, the expression of nicotinic acetylcholine receptor subunits in the lumbar spinal cord following peripheral nerve injury has not been investigated. We examined the expression of the alpha3, alpha4, alpha5, alpha7, beta2, beta3 and beta4 nicotinic subunits in the spinal cord of normal and spinal nerve ligated rats using immunocytochemistry. Two nicotinic subunits were found to have an increased expression following spinal nerve ligation. The number of cells expressing the alpha3 subunit in the dorsal horn increased bilaterally following spinal nerve injury. Also, the number of alpha5 immunoreactive fibers increased significantly ipsilateral to ligation. The expression of the alpha4, alpha7, beta2, beta3 and beta4 subunits was unchanged.We propose that the increased expression of the alpha3 and alpha5 nicotinic subunits may contribute to the mechanical hypersensitivity observed following spinal nerve ligation.

    KOENEN, A. VON, 1889-1891. Das Norddeutsche Unter-Oligocän und seine Mollusken-Fauna; Lieferung I: Vorwort - Strombidae - Muricidae - Buccinidae. Lieferung II: Conidae - Volutidae - Cypraeidae. Lieferung III: Naticidae - Pyramidellidae - Eulimidae - Cerithidae - Turitellidae. 817 p., 52 pls, contemporary hcalf, spine gilt with red label (slightly rubbed but binding still attractive). Library stamps and library number pasted on front cover. The first three volumes of this important standard work on the oligocene molluscs from Germany. The plates are beautifully drawn and of a very high quality. (Available from Hermann Strack (Email: h.l.strack@planet.nl) www.strackbooks.nl)

    Vallejo B. (2005) Inferring the mode of speciation in Indo-West Pacific Conus (Gastropoda: Conidae). Journal of Biogeography 32 (8), 1429–1439.
    Institute of Environmental Science and Meteorology, University of the Philippines, Diliman, 1101 Quezon City, Philippines. E-mail: BMVallejo@up.edu.ph

    Abstract:Aim This study aims to initially explore the mode of speciation in Indo-West Pacific Conus.
    Location: The Indo-West Pacific island arc, Indian and Pacific Oceans.
    Methods: Relating evolutionary divergence in a molecular phylogeny [T.F. Duda & S.R. Palumbi (1999) Proceedings of the National Academy of Science USA, 96, 10272] using node height with modern range extents as a possible measure of allopatric or sympatric speciation following that of T.G. Barraclough, A.P. Vogler & P.H. Harvey [(1999) Evolution of Biological Diversity. Oxford University Press, Oxford] models of sympatric and allopatric speciation.
    Results: The analysis seems to indicate that the relationship of sympatry with node height is not informative. Species that have diverged quite recently show 100% sympatry with the sister species. A clearer signal of recent allopatric speciation is observed in species whose distribution is at the edge of the Indian and Pacific Ocean basins. In the widely distributed Conus ebraeus clade, the relationships of node heights and range extents of the member species support a key prediction of sympatric speciation. In highly ecologically specialized species, there is a smaller degree of sympatry than those species that are less specialized.
    Main conclusions: The modes of speciation models presented in this study are not informative. This suggests that there had been large and possibly rapid changes in range size after speciation in the various clades. This could have been due to the fact that the wide dispersal life-history strategy in the genus had been largely conserved in Conus evolution. There is evidence of sympatric and parapatric speciation in one Conus clade. Overall, the patterns of phylogeny and range distribution when related to the timing of speciation lend circumstantial support to a Neogene centre of origin hypothesis but not to speciation on the Pacific Plate. Speciation is likely to have been associated with the Tethys Sea closure event, with rapid speciation occurring after closure.

    VON KOENEN, 1890. Das N.deutsche Unter-Oligocän & seine Mollusken-Fauna - Lieferung 2: Conidae - Volutidae - Cypraeidae. 310pp., 16pls. Euro 115.00

    Walls, 1978. Cone shells a synopsis of the living Conidae. Publisher: Hong Kong ; Neptune City, N.J. : T.F.H. Publications, 1006pp., num.figs., num.col.pls.ISBN: 0876666284

    West, D.J., Andrews, E.B., Bowman, D., McVean, A.R. and Thorndyke, M.C. (1996) Toxins from some poisonous and venomous marine snails. Comp. Biochem. Physiol. 113C: 1-10.
    Key words: Calcium channels, conotoxins, gastropoda, ion channels, neurotoxins, prosobranhcia, salivary gland, serotonin, venom.
    Topics: Venomous marine snails (Conus Species and the Conotoxins; The Dogwhelk, Nucella Lapillus): Poisonous Marine Snails (Salivary Gland Secretions; Hypobranchial Gland Secretions; Marine Snail Toxins of Dietary Origin);Figure 1. Diagrams of the anterior end of the body of A, Nucella and B, Conus. Table 1. Toxins isolated from marine snails outside the genus Conus. .

    West DJ, Andrews EB, McVean AR, Thorndyke MC, Taylor JD. (1998) Presence of a toxin in the salivary glands of the marine snail Cymatium intermedius that targets nicotinic acetylcholine receptors. Toxicon 36: 25-29.
    School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey, U.K.
    Abstract:Presence of a toxin in the salivary glands of the marine snail Cymatium intermedius that targets nicotinic acetylcholine receptors. Toxicon 36, 25-29, 1998.-We present evidence of a neurotoxin from the salivary glands of Cymatium intermedius that displays acetylcholine-like effects on vertebrate (mouse ileum) and invertebrate (molluscan smooth muscle; molluscan heart; leech body wall) tissues. These effects were completely blocked by (+)-tubocurarine (10-100 muM) but not by atropine (up to 200 muM) suggesting that the toxin targets nicotinic-like acetylcholine receptors. This affirms the proposal that this genus may overcome their prey with a paralytic secretion.

    Whatley, R.E. (2002) Marine mollusks and the skin. Dermatologic Therapy15: 38 -
    Abstract: Human contact with marine mollusks such as shellfish, marine snails, octopuses, and squids may result in human illness including dermatologic disorders. These range from minor traumatic injury of the skin to more serious systemic illnesses that include dermatologic manifestations. Notable among these are dermatologic manifestations of illness caused by toxins from ingested mollusks, stings of the cone snail, and envenomation by the bite of the blue-ringed octopus. Cone snail and blue-ringed octopus envenomations, although rare, can be deadly due to neuromuscular paralysis. Management of dermatologic illnesses caused by marine mollusks depends upon the nature of the exposure. Attention to local measures is usually sufficient for minor cuts and abrasions. Conversely, cone snail and blue-ringed octopus envenomations require immediate attention, possibly including cardiopulmonary resuscitation.

    Whyte, J.M. Pharmacological investigation of the venoms of the marine snails Conus Textile and Conus Geographus. (book was available from Amazon).

    Wils et al., 1979. 2 new Conus species from off Barbados, Lesser Antilles (6pp., 14figs., 2tabs.).

    Wilson, G F, Fisher, T E, Joiner, W J, Olivera, B M, Kaczmarek, L K. (1991). Venom from Conus-Textile Activates A Tetrodotoxin-Sensitive Inward Current in Bag Cell Neurons of Aplysia. 21st Annual Meeting Of The Society For Neuroscience, New Orleans, Louisiana, Usa, November 10-15, (1991. Soc Neurosci Abstr 17 1-2 1991 ASNEE Society for Neuroscience Abstracts 0190-5295 955.

    Xiao W.H. and Bennett G.J. (1995). Synthetic omega-conopeptides applied to the site of nerve injury suppress neuropathic pains in rats. J Pharmacol Exp Ther 274: 666-672. [SNX-111, NIH 95363679.]

    Winn SR, Emerich DF. (2005). Managing chronic pain with encapsulated cell implants releasing catecholamines and endogenous opioids. Front Biosci. 10:367-78.
    Department of Surgery, Division of Plastic and Reconstructive Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA. winns@ohsu.edu

    Abstract: Spinal injections (intrathecal) of norepinephrine and/or opioid agonists are antinociceptive and when administered together may act in synergy. Spinal implants of adrenal chromaffin cells are an effective method for sustained delivery of the analgesic substances norepinephrine and enkephalin to the central nervous system (CNS). One method of packaging and implanting cell-loaded devices into the intrathecal space of recipients is by encapsulating the cell suspensions in a polymer membrane prior to implantation. Cells/tissue packaged within an encapsulating membrane obviate the need for immunosuppressive therapies in transplant recipients. In addition, device output can be quantified prior to implantation, and following the removal of the spinal implant. The ability to retrieve the devices with the present tubular configuration also confers an additional margin of safety over unencapsulated chromaffin cell implants. This paper reviews the research and clinical observations of cellular transplants containing adrenal chromaffin cells for relieving chronic pain. Encapsulated cell technology is discussed with an emphasis on our experiences developing pain-modulating clinical devices. The human-sized prototype devices were loaded with enzymatically isolated bovine chromaffin cells and maintained in vitro for 7 - 8 days in serum-free media. Two days prior to implantation, each device was assayed by static incubation to measure catecholamine and met-enkephalin output, and qualified devices (n = 6) were implanted into the sheep subarachnoid space for 6 weeks. Following a 6 week in life period, the retrieval forces of prototype devices were measured during removal from the subarachnoid space. Static incubation of the devices immediately following retrieval and after a 24 hour re-incubation period were used to quantify norepinephrine and met-enkephalin secretion profiles. This study demonstrated the safety, retrievability and maintenance of pharmacologically active encapsulated chromaffin cell-loaded devices with human implant dimensions.

    Wittekindt, B., Malany, S., Schemm, R., Otvos, L., Maccecchini, M.-L., Laube, B. and Betz, H. (2001) Point mutations identify the glutamate binding pocket of the N-methyl-d-aspartate receptor as major site of Conantokin-G inhibition. Neuropharmacology, 41: 753-762. .
    Abstract: Conantokin-G (Con-G), a gamma-carboxylglutamate (Gla) containing peptide derived from the venom of the marine cone snail Conus geographus, acts as a selective and potent inhibitor of N-methyl-d-aspartate (NMDA) receptors. Here, the effect of Con-G on recombinant NMDA receptors carrying point mutations within the glycine and glutamate binding pockets of the NR1 and NR2B subunits was studied using whole-cell voltage-clamp recording from cRNA injected Xenopus oocytes. At wild-type receptors, glutamate-induced currents were inhibited by Con-G in a dose-dependent manner at concentrations of 0.1-100 muM. Substitution of selected residues within the NR2B subunit reduced the inhibitory potency of Con-G, whereas similar mutations in the NR1 subunit had little effect. These results indicate a selective interaction of Con-G with the glutamate binding pocket of the NMDA receptor. Homology-based molecular modeling of the glutamate binding region based on the known structure of the glutamate binding site of the AMPA receptor protein GluR2 suggests how selected amino acid side chains of NR2B might interact with specific residues of Con-G.

    Yashiro, H.(1939) Fatal bite of Conus geographus. Venus IX (3 - 4), October 1939 (in japanese)

    YEN, T.C. ET AL., 1948-1949. Collection of 5 important papers on molluscs: Yen, Notes on Land and Freshwater Mollusks of Chekiang Province, China (30 p., 1 pl.) / Smith & Gordon, The Marine Mollusks and Brachiopods of Monterey Bay, California, and Vicinity (99 p., 2 pls) / Hanna & Strong, West American Mollusks of the Genus Conus (76 p., 6 pls) and two smaller papers by Ingram on Cypraeidae; All bound together in cloth. Library stamps. All published in Proceedings of the California Academy of Sciences. (Available from Hermann Strack (Email: h.l.strack@planet.nl) www.strackbooks.nl)

    Yuji, N., Nakagawa, Y. and Sakakibara, S. (1983) Synthesis of three disulfide analogs of conotoxin GI: Determination of the secondary structure. In: Peptide Chemistry 1982 (Edited by S. Sakakibara) Protein Research Foundation, Osaka, (1983) pp. 127-132.
    [Conus geographus, disulfide structural isomers, in vivo toxicity, directed synthesis, From these findings we condclue tht the most readily formed conformer had the most potent biological activity. This result seems to conflict with the prevous finding of Gray et al JBC 256: 4734, 1981, that once the natural toxin is reduced, the toxicity cannot be regenerated by reoxidization. Although we have not compared the synthetic materials with the natural toxin, we think conotoxin GI has the type B (2-7;3-13) structure. Elucidation of the solution conformation, structure-activity relationship and mechanism of the pharmacological action should be our next target with this toxin. see also Nishiuchi and Sakakibara (1983), above]

    Yoshiba S. (1984) [An estimation of the most dangerous species of cone shell, Conus (Gastridium) geographus Linne, 1758, venom's lethal dose in humans] Nippon Eiseigaku Zasshi 39:565-572. Japanese. No abstract available.

    Zafaralla, G.C., Ramilo, C., Gray, W.R., Karlstrom, R., Olivera, B.M. and Cruz, L.J. (1988) Phylogenetic specificity of cholinergic ligands: alpha-conotoxin SI. Biochemistry 27: 7102-7105.
    [Abstract:Conus striatus, alpha-conotoxin SI, alpha 3/5 group, fish-hunting, Indo-Pacific]
    Zilch, (1970). Conus gloriamaris, die Zierde des Meeres. 7pp., 3figs., 1col.pl..
     

    List at Molluscs of some older references.
     

    BGL January 99 - December 2004

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