What's New in 2002

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Analgesic Component of Venom (ACV1) from Cone Snails :
see Nature Science Update "Snail toxin could ease chronic pain" by Ingrid Holmes http://www.nature.com/nsu/020715/020715-11.html

Two scientific meetings on Cone Shells/Conotoxins:
(1) International Society of Toxinology (I.S.T.) "6th Asia-Pacific Congress Australia 2002". 8-12 July, 2002. Cairns Colonial Club, Cairns, North Queenland, Australia, followed by
(2) "Venoms to Drugs 2002" 14-19 July, 2002, Heron Island, Great Barrier Reef, Queensland, Australia. - details below


An "Internet Interview" with Bruce Livett: conducted in February 2001 about his scientific work with cone shells and conotoxins (and his interaction with other malacologists and shell collectors), is now available as a downloadable Adobe pdf file. This extensive Intervista web "interview" conducted by Eduardo Moreira for Callostoma was subsequently published (in condensed form) in American Conchologist Volume 30, Number 1, 2002, pp. 5 & 14.

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27 December, 2002

22 December, 2002

    Conus imagery:
    Here are a number of Conus images from the web loosely assembled into an eclectic list for you to browse :

  • Conus fossils : A collection of Conus fossils (biconic shells up to 10 cm) are seen. Its spiral forms a small cone of 6 the 7 rollbacks. Conus is a carnivore that kills its prey with a poisonous venom. It is known from the Cretaceous until the present, some 80 million years of existence (source: João Gonçalves Castanheira , Portugal).

  • Fossil Conus sp.(source: Kevin McCartney, Northern Maine Museum of Science , Maine, USA).

  • Nsan's Cone shell collection. This list of 99 Conus includes Conus catus from the Great Barrier Reef, Australia, a beautiful pink specimen of Conus anemone peronianus from South Australia, a specimen of Conus advertex trawled at 80fathoms off Cape Moreton, Queensland, Conus pergrandis 1210 mm, (mis-named "perglandis" !) and two cones from Fremantle, WA, Australia, Conus boetidus and Conus vexillum.

  • Rueben's Nature Photos from Singapore includes the following photo of Conus ebraeus (Hebrew cones)in their native habitat (Mauritius), put up "to let people know that there are many extraordinary and fascinating organisms still inhabiting parts of our island".

  • Seashell X-rays: Steven Crow, M.D., has created one of the world's best and largest ccollections of seashell X-rays. More than 40 stunning seashells from China, Japan, Australia, The Philippines, Africa, and the Americas fade into their X-rays. Included are the following cone shells: Conus textile, Conus striatus and Conus leopardus.
  • A twisted cone: Conus orbigny (Orbigny's Cone), is rarely straight, but this one is a real twister ! Seen in dorsal view, this twisted and somewhat distorted shell shows evidence of severe damage as a younger shell. Note the failure of the final whorl to match up with the previous whorls. Here is another view (ventral view). View other cones on display at the Universal Trading Company gastropod exhibit.

  • Tony Mortlock has reviewed a book entitled The King Kong Effect by Paul Adirex. According to the information provided, "the author Paul Adirex is an American-educated prominent Thai politician (he is currently Deputy Prime Minister) and businessman. His real Thai name translated into English is Pongpol Adireksarn. His English style of writing is easy to follow, and the stories are very well put together, with a good mix of real and fictional events.
    Published in 1998 by Aries Books (Bangkok), ISBN 9748962032, 378 pages. (The book is available in paperback from Asia Books - Price: Bht 215.00, US$ 4.78). I read this story in a single sitting. Yes it is quite short, but also almost impossible to put down, once you've read the first few pages. The story revolves around a colony of giant Conus geographus which are discovered near the island of Butang in Thailand's Andaman Sea. The fact that these marine moluscs happen to fire deadly darts when threatened is key to the story, which takes place mainly in Phuket and nearby islands. The story involves a former US military attache Byron Clifford whose marine animal research and investigations into his brother's suspicious death in Phuket leads to violent confrontation with Singaporean wildlife collectors, and Thai and American drug smugglers plotting to kill the US President in Phuket. The action takes place on Butang other Andaman Islands such as the Similans and Surins.
    Tony Mortlock happened to visit both the Similans and Surins in January 1996, the date the events in the story unfold, and includes on his webpage a picture of the Surins contemporary to the story.

  • Patty Jansen has a number of paintings and line drawings of shells at Patty's shell art. Included are paintings of the following cones: Conus ammiralis, Conus barthelmeyi, Conus dorreensis, Conus lischkeanus and Conus vexillum

  • Business end of a venomous cone: All features are on display here as we look front end on at a venomous Conus striatus. Take care out there !

20 December, 2002

    Sodium channel toxin from Conus stercusmuscarum:
    Baldomero Olivera and colleagues have reported on a new peptide that inhibits tetrodotoxin-resistant voltage-gated sodium channels such as those found in sensory neurons that convey pain information.
    West PJ, Bulaj G, Garrett JE, Olivera BM and Yoshikami D. (2002) "mu-Conotoxin SmIIIA, a Potent Inhibitor of Tetrodotoxin-Resistant Sodium Channels in Amphibian Sympathetic and Sensory Neurons." Biochemistry. 41:15388-15393
    mu-Conotoxins are a family of peptides from the venoms of predatory cone snails. Previously characterized mu-conotoxins preferentially block skeletal muscle voltage-gated sodium channels. We report here the discovery (via cloning), synthesis, and electrophysiological characterization of a new peptide in this family, mu-conotoxin SmIIIA from Conus stercusmuscarum. Although mu-conotoxin SmIIIA shares several biochemical characteristics with other mu-conotoxins (the arrangement of cysteine residues and a conserved arginine believed to interact with residues near the channel pore), it has distinctive features such as the absence of hydroxyproline. In voltage-clamped dissociated neurons from frog sympathetic and dorsal root ganglia, the peptide inhibited the majority of tetrodotoxin-resistant sodium currents irreversibly; in contrast, tetrodotoxin-sensitive sodium currents were largely unaffected by the peptide. We believe that mu-conotoxin SmIIIA is the first specific antagonist of tetrodotoxin-resistant voltage-gated sodium channels to be discovered. Thus, the peptide provides a new and potentially useful tool to investigate the functional roles of tetrodotoxin-resistant voltage-gated sodium channels, including those that are found in sensory nerves that convey nociceptive information.

17 December, 2002

    Cone shell images updated:
    Giancarlo Paganelli has updated his Cone Shells collection (currently currently 660 images), with the following 10 images ("All the cones are unfiled lip"):
    Conus comatosa PILSBRY, 1904, Philippines, Sulu Sea - 27.2 mm ; and Philippines, Panglao Is. , Bohol - 39.7 mm; Conus emaciatus REEVE, 1849 Philippines, Balaboc, Palawan - 55.2 mm; Conus gradatulus WEINKAUFF, 1875, South Africa - 69.7 mm; Conus lischkeanus WEINKAUFF, 1875, Australia, Yardie Homestead - 34.4 mm; Conus planorbis BORN, 1778, Philippines - 50.3 mm; Conus planorbis f. vitulinus HWASS in BRUGUIÈRE, 1792, Philippines - 56.1 mm; Conus princeps LINNAEUS, 1758, Panama - 40.7 mm; and Conus princeps f. apogrammatus DALL, 1910 Panama - 34.5 mm; Conus recluzianus REEVE, 1844, Philippines, Marinduque Is. - 38.4 mm; and Conus recluzianus f. roseorapum, BERNARDI, 1853, Japan - 45.4 mm. Conus spurius f. quadratus RÖDING, 1798, Panama, Porto Bello - 75.5 mm; Conus varius LINNAEUS, 1758 Fidji - 33.9 mm and Conus zonatus HWASS in BRUGUIÈRE, 1792, Thailand, Andaman Sea, Ko Rayka, Phuket - 57.2 mm

10 December, 2002

    Contulakin-G clinical safety trials:
    Cognetix Inc. announced issuance of a US patent (6,489,298)and the results of their first clinical safety study with Contulakin-G (CGX-1160) for acute and chronic pain (see below). In summary, the company completed an initial safety and pharmacokinetic human clinical study of CGX-1160 in healthy volunteers. A total of 48 individuals were studied, 36 receiving CGX-1160 and 12 receiving placebo, by intravenous administration. No serious adverse events were observed. In animal studies, CGX-1160 has been shown to be effective in models of acute, persistent, chronic inflammatory, post-surgical and neuropathic pain. CGX-1160 has exhibited a wide margin of safety in these animal models.

    Cognetix Announces Issuance Of U.S. Patent On Contulakin-G To Treat Pain; First Clinical Safety Study Completed With CGX-1160
    SALT LAKE CITY, Dec. 5 /PRNewswire/ -- Cognetix, Inc. announced today the issuance of United States patent number 6,489,298 by the U.S. Patent and Trademark Office. The patent covers the use of Contulakin-G (CGX-1160) for the treatment of acute and chronic pain, including pain from cancer, neuropathic pain and inflammatory chronic pain. Contulakin-G is a novel 16-amino acid conopeptide originally isolated from the venom of the marine snail Conus geographus.
    This is the fourth patent in the Company's portfolio covering the composition and use in therapeutics of Contulakin-G, further broadening the proprietary position surrounding the compound. The patent portfolio of Cognetix is comprehensive, with an estate of more than 37 issued U.S. and international patents held by the Company under an exclusive license with the University of Utah Research Foundation. These patents collectively cover hundreds of conopeptides within 17 families, each targeting pharmaceutically important receptors and ion channels.
    "We are excited about the potential of CGX-1160 to treat a broad range of pain syndromes, which is our major therapeutic and development focus," said Thomas B. King, Cognetix President and CEO. "Our goal in 2003 is to continue the aggressive development of the compound."
    Cognetix recently completed an initial safety and pharmacokinetic human clinical study of CGX-1160 in healthy volunteers. A total of 48 individuals were studied, 36 receiving CGX-1160 and 12 receiving placebo, by intravenous administration. No serious adverse events were observed. In animal studies, CGX-1160 has been shown to be effective in models of acute, persistent, chronic inflammatory, post-surgical and neuropathic pain. CGX-1160 has exhibited a wide margin of safety in these animal models.

8 December, 2002

6 December, 2002

    Conantokin-L from Conus lynceus targets NMDA receptors:
    Jimenez EC, Donevan S, Walker C, Zhou LM, Nielsen J, Cruz LJ, Armstrong H, White HS, Olivera BM. (2002) Conantokin-L, a new NMDA receptor antagonist: determinants for anticonvulsant potency. Epilepsy Res 51:73-80

    Conantokins are N-methyl-D-aspartate receptor antagonist peptides found in the venoms of marine cone snails. Current intense interest in this peptide family stems from the discovery of their therapeutic potential as anticonvulsants. It was recently reported that conantokin-R is a highly potent anticonvulsant compound, with a protective index of 17.5 when tested in the audiogenic mouse model of epilepsy. Conantokin-L was characterized from Conus lynceus and found to have extensive homology with conantokin-R, except For the C-terminal amino acids. Although conantokin-L appears almost as potent as conantokin-R in standard in vivo assays for conantokins and NMDA receptor binding assays, it is far less potent as an anticonvulsant, with a protective index of 1.2 in the audiogenic mouse model. The results suggest that the C-terminal sequences of conantokin-R and conantokin-L are a major determinant of their anticonvulsant potency. Copyright 2002 Elsevier Science B.V.

5 December, 2002

    alpha-Conotoxin GID targets alpha3beta2 and alpha-7 nicotinic receptors:
    Nicke A, Loughnan ML, Millard EL, Alewood PF, Adams DJ, Daly NL, Craik DJ, Lewis RJ. (2002) "Isolation, structure and activity of GID, a novel 4/7alpha-conotoxin with an extended N-terminal sequence". J Biol Chem 2002 Nov 4; [epub ahead of print]

    Using assay-directed fractionation of C. geographus crude venom, we isolated alpha-conotoxin GID which acts selectively at neuronal nicotinic acetylcholine receptors (nAChRs). Unlike other neuronally selective alpha-conotoxins, alpha-GID has a four amino acid N-terminal tail, gamma-carboxyglutamate and hydroxyproline residues, and lacks an amidated C-terminus. GID inhibits alpha7 and alpha3beta2 nicotinic nAChRs with IC50 values of 5 nM and 3 nM, respectively, and is at least 1000-fold less potent at the alpha1beta1gama_delta, alpha3beta4, and alpha4bbeta4 combinations. GID also potently inhibits the alpha4beta2 subtype (IC50 150 nM). Deletion of the N-terminal sequence (GIDdelta14) significantly decreased activity at the alpha4beta2 nAChR but hardly affected potency at alpha3beta2 and alpha7 nAChRs, despite enhancing the off-rates at these receptors. In contrast, Arg12 contributed to alpha4beta2 and alpha7 activity but not to alpha3beta2 activity. The three-dimensional structure of GID is well defined over residues 419 with a similar motif to other alpha-conotoxins. However, despite its influence on activity, the tail appears to be disordered in solution. Comparison of GID with other alpha4/7-conotoxins which possess an NNP/O motif in loop II, revealed a correlation between increasing length of the aliphatic side chain in position 10 (equivalent to 13 in GID) and greater alpha7 vs alpha3beta2 selectivity.

    kappaM-conotoxin RIIIK from Conus radiatus:
    Ferber M, Sporning A, Jeserich G, DeLaCruz R, Watkins M, Olivera BM, Terlau H. (2002) "A novel conus peptide ligand for K+ channels."J Biol Chem 2002 Oct 23; [epub ahead of print]

    Voltage-gated ion channels determine the membrane excitability of cells. Although many Conus peptides that interact with voltage-gated Na+ and Ca++ channels have been characterized, relatively few have been identified that interact with K+ channels. We describe a novel Conus peptide that interacts with the Shaker K+ channel, kappaM-conotoxin RIIIK from Conus radiatus. The peptide was chemically synthesized. Although kappaM-conotoxin RIIIK is structurally similar to the omega-conotoxins that are sodium channel blockers, it does not affect any of the sodium channels tested, but blocks Shaker K+ channels. Studies using Shaker K+ channel mutants with single residue substitutions reveal that the peptide interacts with the pore region of the channel. Introduction of a negative charge at residue 427 (K427D) greatly increases the affinity of the toxin, while the substitutions at two other residues, F425 and T449, drastically reduced toxin affinity. Based on the Shaker results, a teleost homolog of the Shaker K+ channel, TSha1 was identified as a kappaM-conotoxin RIIIK target. Binding of kappaM-conotoxin RIIIK is state dependent, with an IC(50) of 20 nM for the closed state and 60 nM at 0 mV for the open state of TSha1 channels.

    omega-Conotoxin GVIA off-rate is correlated with divalent cation concentration:
    Liang H and Elmslie KS (2002) Rapid and reversible block of N-type calcium channels (CaV 2.2) by omega-conotoxin GVIA in the absence of divalent cations. J Neurosci 2002 Oct 15;22(20):8884-90

    Omega-conotoxin GVIA (omegaCGVIA) has been reported to be an irreversible blocker of N-type calcium channels (Ca(V) 2.2). However, recent studies have demonstrated that the omegaCGVIA off-rate is correlated with divalent cation concentration, because increasing [Ba2+]o accelerated the recovery from omegaCGVIA block. This predicts that the dissociation of omegaCGVIA from N-channels will be negligible in the absence of divalent cations. Surprisingly, we find that omegaCGVIA block is rapidly reversible in divalent cation-free (0 Ba2+) external solutions in which current was carried by MA+. The recovery followed a single-exponential time course with tau = 31 sec. Isochronic measurements showed that, at 2 min after the removal of toxin, current returned to 86% of control in 0 Ba2+ compared with 19% in 3 mm Ba2+. The off-rate of omegaCGVIA from N-channels was dependent on [Ba2+]o, because, at an intermediate concentration (3 microm Ba2+), N-current recovered with tau = 64 sec, significantly slower than that in 0 Ba2+ but faster than in 3 mm Ba2+. Recovery from omegaCGVIA block was also observed when Cs+ or Na+ carried the current in divalent cation-free conditions. The off-rate was sensitive to [Ba2+]o only during washout, because current recovered slowly in the presence of 3 mm Ba2+, even after it was blocked in 0 Ba2+. Assuming that the toxin is a pore blocker, our findings are consistent with a model in which Ba2+ interacts at a site on the extracellular surface of the channel to regulate omegaCGVIA dissociation from N-channels.

    alpha-5 and alpha-6 nAChR subunits contribute to neuronal nAChRs on striatal dopaminergic terminals :
    Zoli M, Moretti M, Zanardi A, McIntosh JM, Clementi F, Gotti C. (2002) "Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum".J Neurosci 2002 Oct 15;22(20):8785-8789

    Neuronal nicotinic acetylcholine receptors (nAChRs) expressed on mesostriatal dopaminergic neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Using immunoprecipitation and ligand-binding techniques, we have shown that both alpha6beta2* and alpha4(nonalpha6)beta2* nAChRs are expressed in the caudate-putamen and that only alpha6* nAChRs can bind alpha-conotoxin MII and methyllycaconitine with affinities of 1.3 and 40 nm, respectively. Further studies performed on 6-hydroxydopamine-lesioned striatum led to the identification of nAChR subtypes selectively expressed on dopaminergic terminals [alpha4alpha5beta2, alpha4alpha6beta2(beta3), and alpha6beta2(beta3)], nondopaminergic neuronal structures (alpha2alpha4beta2), or both structures (alpha4beta2). The identification of the nAChRs expressed on striatal dopaminergic terminals opens up the possibility of developing selective nAChR ligands active on dopaminergic systems and associated diseases, such as Parkinson's disease.

    alpha-conotoxin ImII from Conus imperialis: a probe for a novel antagonist binding site, on the alpha7 nicotinic acetylcholine receptor. :
    Ellison MA, McIntosh JM and Olivera BM. (2002) "alpha -Conotoxins ImI and ImII: Similar alpha 7 nicotinic receptor antagonists act at different sites".J Biol Chem 2002 Oct 15; [epub ahead of print]

    A novel conotoxin, alpha-conotoxin ImII ({alpah}-CTx ImII), identified from Conus imperialis venom ducts, was chemically synthesized. A previously characterized C. imperialis conotoxin, alpha-conotoxin ImI (alpha-CTx ImI), is closely related; nine out of 12 amino acids are identical. Both alpha-CTx ImII and alpha-CTx ImI functionally inhibit heterologously expressed rat alpha7 nAChRs with similar IC(50) values. Furthermore, the biological activities of intracranially applied alpha-CTx ImI and alpha-CTx ImII are similar over the same dosage range, and are consistent with alpha7 nAChR inhibition. However, unlike alpha-CTx ImI, alpha-CTx ImII was not able to block the binding of alpha-bungarotoxin (alpha-BgTx) to alpha7 nAChRs. alpha-Conotoxin ImI and alpha-BgTx binding sites have been well characterized as overlapping and located at the cleft between adjacent nAChR subunits. Since alpha-CTx ImI and alpha-CTx ImII share extensive sequence homology, the inability of alpha-CTx ImII to compete with alpha-BgTx is surprising. Furthermore, functional studies in oocytes indicate that there is no overlap between functional binding sites of alpha-CTx ImI and alpha-CTx ImII. Like alpha-CTx ImI, the block by alpha-CTx ImII is voltage-independent. Thus, alpha-CTx ImII represents a probe for a novel antagonist binding site, or microsite, on the alpha7 nAChR.

2 December, 2002

    Freak Cones:
    David Pleuvret : is a collector of Conus from the Reunion Islands, and also likes collecting "freak" Conus, among which are images of the following freak cones: Conus magus, Conus malacanus, Conus marmoreus,Conus miles, Conus mindanus, Conus monile, Conus planorbis, Conus radiatus, Conus regius, Conus striatus, Conus subfloridus, Conus sulcatus, Conus tessulatus, Conus turvus, Conus urashimanus and Conus vexilum sumatrensis.

29 November, 2002

    Conotoxin CVID defines a New Calcium Channel subtype:
    Dr. Richard Lewis and colleagues from The University of Queensland, Australia, have revealed a new type of calcium channel in preganglionic parasympathetic neurons through use of the novel omega conotoxin CVID from Conus catus.
    Adams DJ, Smith AB, Schroeder CI, Yasuda T, Lewis RJ. (2002) "omega-Conotoxin CVID inhibits a pharmacologically distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals". J Biol Chem 278: 4057-4062
    Neurotransmitter release from preganglionic parasympathetic neurons is resistant to inhibition by selective antagonists of L-, N-, P/Q-, R- and T-type calcium channels. In the present study, the effects of different omega-conotoxins from genus Conus were investigated on current flow through cloned voltage-sensitive calcium channels expressed in Xenpous oocytes and nerve-evoked transmitter release from the intact preganglionic cholinergic nerves innervating the rat submandibular ganglia. Our results indicate that omega-conotoxin CVID from C. catus inhibits a pharmacologically distinct voltage-sensitive calcium channel involved in neurotransmitter release, whereas omega-conotoxin MVIIA had no effect. omega-Conotoxin CVID and MVIIA inhibited depolarization-activated Ba(2+) currents recorded from oocytes expressing N-type but not L- or R-type calcium channels. High affinity inhibition of the CVID-sensitive calcium channel was enhanced when position 10 of the omega-conotoxin was occupied by the smaller residue Lysine, as found in CVID, instead of an Arginine as found in MVIIA. Given that relatively small differences in the sequence of the N-type calcium channel alpha(1B) subunit can influence omega-conotoxin access (Feng, Z. P., Hamid, J., Doering, C., Bosey, G. M., Snutch, T. P. and Zamponi, G. W. (2001) J. Biol. Chem. 276,15728-15735), it is likely that the calcium channel in preganglionic nerve terminals targeted by CVID is a N-type (Ca(v)2.2) calcium channel variant.

24 November, 2002

    West-African Cones:
    Paulo Granja & Gonçalo Rosa of Low-Tide Shells provide information on shells from the West African Coast. Their aim is to provide images of shells covering all the patterns, colours and forms of a species. The inclusion of outstanding shells it is not a priority. Included in their compilation of World Wide Conidae are images of some 60 West African Conus species. The site is always receptive to inclusion of new information.

23 November, 2002

3 November, 2002

    Conotoxin diversity - alpha Conotoxin AuIB:
    Dutton, J.L., Bansal, P.S., Hogg, R.C., Adams, D.J., Alewood, P.F. and Craik, D.J. (2002) A new level of conotoxin diversity: a non-native disulfide bond connectivity in alpha-conotoxin AuIB reduces structural definition but increases biological activity. J Biol Chem. 277: 48849-48857.
    "Alpha-conotoxin AuIB and a disulfide bond variant of AuIB have been synthesised to determine the role of disulfide bond connectivity on structure and activity. Both of these peptides contain the 15 amino acid sequence GCCSYPPCFATNPDC, with the globular (native) isomer having the disulfide connectivity Cys(2-8, 3-15) and the ribbon isomer having the disulfide connectivity Cys(2-15, 3-8). The solution structures of the peptides were determined by NMR spectroscopy and their ability to block the nicotinic acetylcholine receptors on dissociated neurons of the rat parasympathetic ganglia was examined. The ribbon disulfide isomer, while having a less well defined structure, is suprisingly found to have approximately ten times greater potency than the native peptide. To our knowledge this is the first demonstration of a non-native disulfide bond isomer of a conotoxin exhibiting a greater biological activity than the native isomer.
    [NOTE: for more information about alpha-conotoxins, see Dutton, J.L. and Craik, D.J. (2001) alpha-Conotoxins: nicotinic acetylcholine receptor antagonists as pharmacological tools and potential drug leads. Curr Med Chem. 8:327-344. (Review). BGL]

    Conus pappiliferus:
    Patty Jansen has a nice image of a Conus pappiliferus on her web page http://www.capricornica.com/nathist/con_papp.htm. This Cone shell can be found intertidally under stones on the coast of New South Wales, Australia. There are two other species that can be found here: Conus anemone and Conus aplustre. The shell of the first species is spirally ribbed all over, and the second species is much smaller, and the shell is violet inside.
    These small southern Australian Cone shells do not have the potent poison of their northern counterparts. Whereas all Cones shells are capable of delivering a sting, the sting of these smaller ones will hardly be more serious than a bee sting. Yet, it is better to be safe than sorry. Don't pick up Cone shells at all. 'If it's a Cone, leave it alone' the saying goes.

    Cone shells of Marie-Françoise Fontaine:
    Take up the invitation to visit the web page of Marie-Françoise FONTAINE, Nice, France, a long-term member of the A.F.C (French Association of Conchology) who specializes in shells from Mayotte, Philippines, Zanzibar and Madagascar. Here you can access her list of Conus for sale. She currently has images of the following cone shells on sale Conus gloriamaris, Conus miles and Conus fuscatus dautzenbergi.
    In addition, she has her private collection of cone shells on view. Included are the following interesting (and unusual) Conus specimens : Conus bandanus Mayotte (and dorsal aspect), Conus bockii with double spire, Conus dusavelli Philippines, Conus fuscatus dautzenbergi, two nice specimens of Conus gubernator Nosy Bé, (2), a collection of Conus janus, four specimens of Conus litoglyphus, (2), (3), (4), numerous specimens of Conus maldivus, (2), (3), (4), (5), (6), (7), and some with periostracum, three specimens of Conus namocanus, (2), (3), a box of Conus shikamai, and a freak Conus tessulatus.

12 October, 2002

    Octopi as Cone shell predators:
    Roland Anderson, Puget Sound Curator, The Seattle Aquarium, asked members of the CONCH-L mail list whether "octopuses ever eat cone shells". In answer to this question and whether anyone had ever seen a drilled cone shell, by an octopus or maybe by a naticid snail?, Don Barclay (of 'Cone Wars' fame) answered as follows:
    "Octopi will kill cone snails, and sometimes they eat them.
    A little over a year ago I had a small Octopus vulgaris in my aquarium, and had the opportunity to watch it interact with the cone shells that lived there. It would often "wrap up" the cones, and appeared to be trying to eat them, but was never successful as far as I could tell. However, when we tried some experiments with a larger Octopus cyanea, it was a different story.
    We started with a plastic "kiddie" swimming pool, about six feet wide and a foot deep, with coral rubble and some slabs in the bottom and Astroturf around the edges to keep the octopus from crawling out. We then dragged an empty Conus textile shell around the pool with a piece of fishing line, hoping to see whether the octopus reacted to the pattern on shell, recognizing it as a threat by sight (Conus textile venom is deadly to an octopus). The typical result was that the octopus would extend one tentacle and push the shell away. When a live Conus textile was introduced, the octopus essentially froze--not moving away, but not pushing the live snail away either. The cone showed little or no interest in the octopus, and crawled away. When the cone was moved back beside the octopus, the reaction was the same, but after repeating this several times the octopus seemed to become agitated, and finally pushed the snail away with its tentacle.
    Since we hadn't had much of a reaction from the Conus textile introduction, we tried the same thing with a Conus striatus, a piscivorous cone whose venom isn't dangerous to other molluscs. The Octopus cyanea treated the C. striatus much like he had treated the empty Conus textile shell, pushing it away with a tentacle if it got too close. Since it seemed to be unconcerned about the Conus striatus, I put 5 others in the pool, figuring they would meander safely around the pool until I took them to Hopkins Marine Lab a couple of weeks later. Everything was fine for several days, but one morning when I went to check on "Oscar" I found one of the cone shells empty, and part of the animal floating on the surface, with most of the foot eaten. I also noticed that one of the airstones I was using to aerate the pool appeared "fuzzy," and when I inspected it I found that the "fuzz" was about fifteen Conus striatus teeth, all embedded in the pumice. Evidently the water movement alone was enough to prompt the cones to fire their harpoons, no fishy smell required.
    The next morning started the same way, with another cone shell having been killed. The animal had been completely removed from the shell, but even less had been eaten from this one than the one the previous day. It made me wonder if the octopus had killed the first one because it was hungry (it had been eating crabs regularly) or if it had been receiving the "airstone treatment," and was tired of being stung by the cones.
    That afternoon when I returned from snorkeling I addedseveral other Conus striatus to the pool, by now aware that they might not all survive until I had the chance to take them to Hopkins. Turns out I was right. The next morning the pool surface was covered with slime and pieces of Conus striatus animals, so many pieces in fact that it looked like there must have been ten times as many cones in the pool as there actually were. Every cone in the pool had been killed overnight by the octopus, each one pulled from its shell and torn to bits.
    I'll let you make your own guesses as to "why" Oscar killed the cones. But he was very effective at it in any case, and didn't need to break the shell or drill it to remove the animals.

    As a footnote, I introduced a wide variety of molluscs to the pool as potential food for the Octopus cyanea, but the octopus would only occasionally kill one of them. It definitely preferred crustaceans, and would only eat molluscs if it had gone several days without being fed crabs or shrimp."

10 October, 2002

    Novel alpha-conotoxin is a potent analgesic:WO 02/079236 A1 :
    This International Patent Application Patent, Application WO 02/079236 A1, entitled "ALPHA CONOTOXIN PEPTIDES WITH ANALGESIC PROPERTIES" by Bruce Livett, Zeinab Khalil, Kenwyn Gayler, John Down, David Sandall and David Keays from the University of Melbourne, Parkville, Victoria, Australia, was published on October 10, 2002 .
    "Abstract This invention relates to novel alpha-conotoxin-like peptides comprising the following sequence of amino acids: Xaa1CCSXaa2Xaa3Xaa4CXaa5Xaa6Xaa7Xaa8Xaa9Xaa10Xaa11C-NH2 in which Xaa1 is G or D; Xaa3 is proline, hydroxyproline or glutamine; each of Xaa2 to Xaa8 and Xaa11 is independently any amino acid; Xaa9 is proline, hydroxyproline or glutamine; Xaa10 is aspartate, glutamate or gamma-carboxyglutamate; Xaa11 is optionally absent; and the C-terminus is optionally amidated, with the proviso that the peptide is not alpha-conotoxin Ep1 or alpha-conotoxin Im1. The peptides are useful in the treatment or prevention of pain, in recovery from nerve injury, and in the treatment of painful neurological conditions such as stroke.

    Additional information: The lead compound, an alpha-conotoxin of 16 amino acids, is a neuronal-type nicotinic receptor anatagonist. It blocks pain in an animal (rat) model of chronic neuropathic pain (the CCI model) and in addition, accelerates the rate of functional recovery from a nerve injury. Applications for this peptide and analogues include morphine-resistant neuropathic pain, shingles, diabetic leg ulcer pain, AIDS pain and cancer pain. Being an alpha-conotoxin it acts by a different mechanism to that used by ziconotide and the omega conotoxins that are being developed for pain prevention and is therefore unlikely to have the same side effects. It is also smaller in size and should therefore be more bioavialable. The compound has been termed ACV1 (Analgesic Component of Venom) for commercial purposes and is presently being evaluated for its potential as an analgesic drug for human use. ACV1 is at a preliminary stage of laboratory investigation and it is hoped will progress to clinical trials over the next 5-10 years.

    A report on ACV1 is available on-line at Nature Science Update: http://www.nature.com/nsu/020715/020715-11.html and in
    Drug Discovery Today 7: (17) 885-886, September 2002 issue.

28 September, 2002

    Hand lists still available for molluscs:
    Dr Mary B. Seddon, Head of Mollusca at the Department of Biodiversity & Systematic Biology, National Museums & Galleries of Wales, Cathays Park, Cardiff, has informed us via the CONCH-L listserver that The Melvill-Tomlin mollusc collection documentation is now almost complete, and she expects to have all items in this collection available as on-line databases with a search facility within the next few months. (At present only part of the collection records are searchable on-line). A search for Species = Conus resulted in a list of 793 records. The current holdings can be viewed at:
    http://zoology.nmgw.ac.uk:591/Museum/mollusca_how.htm

    Those of you who have used these collections will be aware that they used to produce printed handlists to the collection [eg. The handlist on Conacea (Conidae). Compiled by A. Trew 1982, comprises 39 pages.] The publication of these handlists stopped in 1996. Since then no further handlists have been produced. They are currently reviewing their need to store handlists to the collections in Cardiff. They have a some handlists available for exchange with sister institutions. The list of handlists can be viewed at: http://zoology.nmgw.ac.uk:591/Museum/mol_handlist.htm
    If you wish to considered for receipt of these handlists please send an e-mail to: Harriet Wood, Collection Manager: Mollusca : Harriet.Wood@nmgw.ac.uk (NB: The NMGW e-mail system will only handle mails that are less than ~1.5 mB size. Any large mails with images can be dropped onto their ftp server. Please send send e-mail to request FTP public access privileges).

23 September, 2002

    Analgesic conotoxins from C.catus, C.geographus and C.magus:
    Prof. Jim Angus and colleagues Christine Wright and David Scott from the Department of Pharmacology, University of Melbourne, Victoria 3010, Melbourne, Australia have shown in this paper (see below) that intrathecal omega-conotoxins are effective in attenuating tactile allodynia in the rat without significantly affecting acute nociceptive responses. omega-Conotoxin CVID had similar potency to omega-conotoxin MVIIA but showed less toxicity in the therapeutic range.

    Scott D, Wright C, and Angus J. (2002) Actions of intrathecal omega-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. Eur J Pharmacol. 451: 279-286

    Abstract: Agents which decrease conductance of N-type voltage-gated Ca(2+) channels have been shown to attenuate measures of neuropathic pain in animal models and to provide symptom relief in humans. The omega-conotoxins have demonstrated efficacy but have a low therapeutic index. We have investigated the effects of a new omega-conotoxin, CVID (AM-336), and compared them with omega-conotoxin GVIA (SNX-124), omega-conotoxin MVIIA (SNX-111) and morphine in a spinal nerve ligation model of neuropathic pain in the rat. The ED(50) (and 95% CI) for attenuation of tactile allodynia by intrathecal administration for omega-conotoxin CVID, GVIA, MVIIA and morphine was 0.36 (0.27-0.48), 0.12 (0.06-0.24), 0.32 (0.23-0.45) and 4.4 (2.9-6.5) ug/kg, respectively. Only morphine significantly prolonged acute tail flick responses (ED(50) 2.3 (1.1-4.9) ug/kg). Of the omega-conotoxins, omega-conotoxin CVID showed the highest ratio of efficacy to behavioural toxicity. These observations show that intrathecal omega-conotoxins are effective in attenuating tactile allodynia in the rat without significantly affecting acute nociceptive responses. omega-Conotoxin CVID had similar potency to omega-conotoxin MVIIA but showed less toxicity in the therapeutic range.

17 September, 2002

    A new Conus from north of the Flores Sea, Indonesia:
    [Extracted from an article by Felix Lorenz (Germany), and communicated by Jon Singleton to Australasian Shell News, No. 115, p.6, September 2002.]
    Lorenz, Felix (2001) "Notes on some species of Conidae and Cypraeidae from Indonesia with the description of Conus empressae sp. non (Mollusca: Gastropoda)." Schriften zur Malakozoologie, 18: 15-20.

    "During a dive expedition travelling from Bali to Darwin through the Indonesian Archipelago, a new Conus species was found at two areas south of Sulawesi: the Pulau Pulau Sabalana archipelago, and Batu Ata Island, both at the northern end of the Flores Sea.
    The new species was named Conus empressae, Lorenz, 2001, after the expedition vessel.
    The shell is rather small, up to 25mm, and heavy, narrow. The spire is elevated. The protoconch and the first four whorls are white, later whorls are brown to purple-brown. The last whorl is brown to pinkish brown, with two grey zones around the midle and the anterior end of the last whorl. The entire last whorl is covered with thin brown encircling lines.
    Lorenz remarks that the species is most similar to C. boeticus, from which it can be separated by its white protoconch and the absence of the subsurural groove. There are also subtle differences in the shape of the last whorl and the colour. C. pauperculus has a purple, rather than brown background and has a more rounded shoulder."
    Photographs are provided which show Conus empressae Lorenz, 2001. The holotype WAM S14001 and one from the John Singleton collection. Both from Batu Ata Island, S. of Sulaesi, Indonesia.

17 September, 2002

    An unknown Cone from Darwin:
    Alan Klishans from Nightcliff, Northern Territory, Australia, reported in the Newsletter of the Malacological Society of Australasia, Australasian Shell News No. 114, June 2002, p.8, that "On Saturday 11 September, 1999 a 45 mm rather attractive cone shell was found in Darwin Harbour. It is similar in shape to Conus achatinus Gmelin, 1791, which in Darwin is more narrow than usual for this species, but has a smaller and rounder operculum." Three specimens of this unknown cone have been collected, one live (49mm), two dead (45mm). A photo is provided. The live-collected specimen has been preserved in 70% ethanol, together with an animal of C. achatinus, collected on the same day in the same locality. This unknown Conus species is narrower than Conus achatinus and displays a different pattern. The spire has no blotches or markings, but has a narrow hand close to the sutures, whose colour is that of the last whorl. The apical whorls are orange pink in colour and the protoconch is larger than that in C. achatinus. The animal, is paler and had a shorter, thicker proboscis. The cone was distinct from the other two species of cone common to Darwin Harbour, C. trigonus Reeve, 1848 (= C. badius Kiener, 1843) , and C. austroviola Rockel & Korn, 1991 (= C. viola Cernohorsky, 1977) both by shape and cell thickness. It appears closest to Conus magus Linne, 1758, but has rounded shoulders and there is no evidence of dashes in the pattern on the last whorl. A number of collectors in Darwin are convinced that is a distinct species.

    Conus sydneyensis back from obscurity:
    Jon Singleton from Geraldton, Western Australia, reported in the same issue of the Australasian Shell News that "after a generation in obscurity, C. sydneyensis is now slowly attaining publicity as Sydney's special Conus." The species was described and named by G.B. Sowerby III in 1887, a small 24 x 12mm cone with a type locality of Port Jackson, NSW, Australia. There appear to be no records of C. sydneyensis for the next 30 years. Specimens were provided to the British Museum, the South Australian Museum, and the Dautzenberg collection held in Brussels. With the start of prawn trawling operations in NSW in the late 1950s, several "new" species were discovered, including a new Conus trawled East of Stanwell Park, NSW, and named Conus illawara by Garrard in 1961. It was not until 1980 that it was realised that C.illawara was the same as the long-forgotten Conus sydneyensis. "illawara" is an old aboriginal name that means 'plentiful place by the sea'. Not so plentiful are specimens for collectors. There have been no new specimens for over 20 years! The whereabouts of Sowerby's type specimen is unknown. However, the old name 'sydneyensis' appears to be having a new lease of life with the cone being illustrated under this name in the latest Cone book.

    P-Conotoxins exhibit structural diversity:
    Miles LA, Dy CY, Nielsen J, Barnham KJ, Hinds MG, Olivera BM, Bulaj G, and Norton RS from the NMR Laboratory, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia have published on the "Structure of a novel P-superfamily spasmodic conotoxin reveals an inhibitory cystine knot motif". J Biol Chem 277(45):43033-43040 (2002).

    Abstract: Conotoxin gm9a, a putative 27-residue polypeptide encoded by Conus gloriamaris, was recently identified as a homologue of the spasmodic peptide, tx9a, isolated from the venom of the mollusc-hunting cone shell Conus textile (Lirazan, M. B., Hooper, D., Corpuz, G. P., Ramilo, C. A., Bandyopadhyay, P., Cruz, L. J., and Olivera, B. M. (2000) Biochemistry 39, 1583-1588). The Conus gloriamaris spasmodic peptide has been synthesized, and the refolded polypeptide was shown to be biologically active using a mouse bioassay. The chemically synthesized gm9a elicited the same symptomatology described previously for natively folded tx9a, and gm9a and tx9a were of similar potency, implying that neither the two gamma-carboxyglutamate (Gla) residues found in tx9a (Ser(8) and Ala(13) in gm9a) nor Gly1 (Ser(1) in gm9a) are crucial for biological activity. We have determined the three-dimensional structure of gm9a in aqueous solution, and demonstrated that the molecule adopts the well-known Inhibitory Cystine Knot (ICK) motif constrained by three disulfide bonds involving Cys(2)-Cys(16), Cys(6)-Cys(18) and Cys(12)-Cys(23). Based on the gm9a structure, the sites of Gla substitution in tx9a are in loops located on one surface of the molecule, which is unlikely to be involved directly in receptor binding. Because this is the first structure reported for a member of the newly defined P-superfamily conotoxins, a comparison has been made with structurally-related conotoxins. This shows that the structural scaffold that characterizes the P-conotoxins has the greatest potential for exhibiting structural diversity amongst the robust ICK-containing conotoxins, a finding that has implications for functional epitope mimicry and protein engineering.

    Marshall J, Kelley WP, Rubakhin SS, Bingham JP, Sweedler JV, Gilly WF.(2002) "Anatomical correlates of venom production in Conus californicus". Biol Bull. 203(1):27-41.

    Abstract: Like all members of the genus, Conus californicus has a specialized venom apparatus, including a modified radular tooth, with which it injects paralyzing venom into its prey. In this paper the venom duct and its connection to the pharynx, along with the radular sac and teeth, were examined using light and transmission electron microscopy. The general anatomy of the venom apparatus resembles that in other members of the genus, but several features are described that have not been previously reported for other species. The proximal (posterior) quarter of the venom duct is composed of a complex epithelium that may be specialized for active transport rather than secretion. The distal portion of the duct is composed of a different type of epithelium, suggestive of holocrine secretion, and the cells display prominent intracellular granules of at least two types. Similar granules fill the lumen of the duct. The passageway between the lumen of the venom duct and pharynx is a flattened branching channel that narrows to a width of 10 micro m and is lined by a unique cell type of unknown function. Granular material similar to that in the venom duct was also found in the lumen of individual teeth within the radular sac. Mass spectrometry (MALDI-TOF) demonstrated the presence of putative peptides in material derived from the tooth lumen, and all of the more prominent species were also evident in the anterior venom duct. Radular teeth thus appear to be loaded with peptide toxins while they are still in the radular sac.

1 September, 2002

22 August, 2002

21 August, 2002

    Conus envenomations:
    John Singleton, Conus expert from Geraldton, Western Australia, has been keeping track of envenomations by cone snails over the past 40 + years. He has contributed the following accounts of Conus stings for our information.

    Cone Shells from the Alboran Sea and NW Africa:
    José María Hernández Otero & Franco Gubbioli have updated their Alboran Shells website (dedicated to marine shells of Alboran Sea and North West Africa). Included are the following CONIDAE :
    Conus bellocqae van Rossum, 1996 - 57/79mm, Guinea, Conus bruguieresi Kiener, 1843 - 25mm, Senegal, Conus cacao Ferrario, 1993 - 25mm, 27mm, Senegal, Conus ermineus Born, 1778 - 56mm, 72mm, Guinea, Conus genuanus Linné, 1758 - 55mm, 79mm, Guinea, Conus genuanus freak Linné, 1758 - freak, 60mm, Guinea, Conus cf. guanche Lauer, 1993 - 26/34mm, Canary Is., Conus cf. guanche freak Lauer, 1993 - freak, 27mm, Canary Is., Conus guinaicus Hwass, 1792 - 30/55mm, Canary Is., Conus_hybridus"> Kiener, 1845 - 36mm, 39mm, Senegal, Conus mediterraneus Hwass in Bruguiere, 1792 28mm, Alboran Sea, Conus mediterraneus Hwass in Bruguiere, 1792 - freak, 21mm, Alboran Sea, and Conus mercator Linné, 1758 - 28mm, 33mm, 38mm, Senegal . From collection of CONIDAE at Alboran Shells. Images of this site are © of José María Hernández Otero & Franco Gubbioli.

    Marie Smith and colleagues from The University of Queensland have reported further on the analgesic properties of omega-conotoxin CVID (AM336) from Conus catus and compared its effects with those of omega-conotoxin MVIIA (Ziconotide, Prialt) from Conus magus.
    Smith, M.T., Cabot, P.J., Ross, F.B., Robertson, A.D. and Lewis RJ (2002) 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. Pain 96:119-127.

    Abstract: 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.

18 August, 2002

    Some conotoxin publications:
    Horvath G, Brodacz B, Holzer-Petsche U. (2002) Blood pressure changes after intrathecal co-administration of calcium channel blockers with morphine or clonidine at the spinal level. Naunyn Schmiedebergs Arch Pharmacol 366:270-275 Department of Physical Therapy, Faculty of Health Science, University of Szeged, Hungary.

    Abstract: Opioids, alpha(2)-adrenoceptor agonists and blockers of voltage-gated calcium channels have been attributed antinociceptive activity, but only few studies have investigated their influence on the haemodynamic parameters. This study was performed to examine the changes in the mean arterial blood pressure (MAP) after intrathecal (i.t.) co-administration of morphine or clonidine with drugs blocking L- or N-type voltage gated calcium channels (verapamil and omega-conotoxin MVIIA, respectively) in anaesthetized rats. Lower doses of clonidine (0.01-5 micro g i.t.) produced dose-dependent decreases in MAP, while the highest dose of clonidine (20 micro g i.t.) produced a pressor response. The administration of morphine (0.01-20 micro g i.t.) caused only minor decreases of blood pressure and these appeared not to be dose dependent. Both omega-conotoxin MVIIA (1 ng-10 micro g i.t.) and verapamil (1-100 micro g i.t.) at higher doses decreased blood pressure significantly. Omega-Conotoxin MVIIA caused a sustained decrease in MAP, while the effect of verapamil was short-lasting. Co-administration of morphine with verapamil or omega-conotoxin MVIIA led to dose-dependent and sustained decreases in blood pressure. The co-administration of omega-conotoxin MVIIA with clonidine did not influence the effect of clonidine significantly. In contrast, the combination of higher doses of verapamil with clonidine caused far greater blood pressure decreases than saline, verapamil or clonidine treatments alone.These data suggest that the calcium channel blockers differentially influence the cardiovascular effect of the well-known antinociceptive drugs morphine and clonidine after intrathecal co-administration.

    Kitayama M, Hirota K, Kudo M, Kudo T, Ishihara H, Matsuki A. (2002) Inhibitory effects of intravenous anaesthetic agents on K(+)-evoked glutamate release from rat cerebrocortical slices. Involvement of voltage-sensitive Ca(2+) channels and GABA(A) receptors. Naunyn Schmiedebergs Arch Pharmacol 366: 246-253 Department of Anesthesiology, University of Hirosaki, School of Medicine, Hirosaki 036-8563, Japan.

    Abstract:It is widely accepted that most general anaesthetic agents depress the central nervous system (CNS) by potentiation or activation of the GABA(A) receptor-mediated Cl(-) conductance. These agents also reportedly inhibit voltage-sensitive Ca(2+) channels (VSCCs), thus depressing excitatory transmission in the CNS. However, in this regard there are few functional data at the level of neurotransmitter release. In this study we examined the effects of VSCC antagonists and a range of intravenous anaesthetic agents on K(+)(40 mM)-evoked glutamate release from rat cerebrocortical slices in the absence and presence of the GABA(A) receptor antagonist bicuculline (100 micro M). We employed both selective and non-selective VSCC antagonists, the anaesthetic barbiturates thiopental, pentobarbital and phenobarbital, the non-anaesthetic barbiturate barbituric acid, the non-barbiturate anaesthetics alphaxalone, propofol and ketamine and the GABA(A) receptor agonist, muscimol. Glutamate released into the incubation medium was determined by a glutamate dehydrogenase-coupled assay. omega-Agatoxin IV(A) (P-type VSCC), omega-conotoxin MVII(C) (P/Q-type VSCC) and Cd(2+) (non-selective) essentially abolished glutamate release whilst nifedipine (L-type VSCC) and omega-conotoxin GVI(A) (N-type VSCC) reduced release by less than 30%. The concentrations producing 50% of the maximum inhibition (IC(50)) for thiopental, pentobarbital, phenobarbital, alphaxalone, propofol and ketamine were (in micro M) 8.3, 22, 112, 6.3, 83 and 120, respectively. Barbituric acid produced a small (about 20%) inhibition. With the exception of ketamine, the IC(50) values for these anaesthetic agents were increased threefold by bicuculline (100 micro M). In addition, muscimol significantly inhibited release by 26% with an IC(50) of 1.1 micro M. In summary, a range of anaesthetic agents at clinically achievable concentrations inhibit glutamate release and this inhibition of release appears to be due mainly to direct inhibition of P/Q-type VSCCs, although activation of the GABA(A) receptor plays a role in this response.

    Giovannini F, Sher E, Webster R, Boot J, Lang B. (2002)Calcium channel subtypes contributing to acetylcholine release from normal, 4-aminopyridine-treated and myasthenic syndrome auto-antibodies-affected neuromuscular junctions. Br J Pharmacol 136:1135-1145 Neuroscience Group, Institute of Molecular Medicine, John Radcliffe Hospital, Headington OX3 9DU, U.K. Eli Lilly and Research Centre Lim., Erl Wood Manor, Windlesham, Surrey GU20 6PH, U.K.

    Abstract: 1. Acetylcholine release at the neuromuscular junction relies on rapid, local and transient calcium increase at presynaptic active zones, triggered by the ion influx through voltage-dependent calcium channels (VDCCs) clustered on the presynaptic membrane. Pharmacological investigation of the role of different VDCC subtypes (L-, N-, P/Q- and R-type) in spontaneous and evoked acetylcholine (ACh) release was carried out in adult mouse neuromuscular junctions (NMJs) under normal and pathological conditions. 2 omega-Agatoxin IVA (500 nM), a specific P/Q-type VDCC blocker, abolished end plate potentials (EPPs) in normal NMJs. However, when neurotransmitter release was potentiated by the presence of the K(+) channel blocker 4-aminopyridine (4-AP), an omega-agatoxin IVA- and omega-conotoxin MVIIC-resistant component was detected. This resistant component was only partially sensitive to 1 micro M omega-conotoxin GVIA (N-type VDCC blocker), but insensitive to any other known VDCC blockers. Spontaneous release was dependent only on P/Q-type VDCC in normal NMJs. However, in the presence of 4-AP, it relied on L-type VDCCs too. 3 ACh release from normal NMJs was compared with that of NMJs of mice passively injected with IgGs obtained from patients with Lambert-Eaton myasthenic syndrome (LEMS), a disorder characterized by a compromised neurotransmitter release. Differently from normal NMJs, in LEMS IgGs-treated NMJs an omega-agatoxin IVA-resistant EPP component was detected, which was only partially blocked by calciseptine (1 micro M), a specific L-type VDCC blocker. 4 Altogether, these data demonstrate that multiple VDCC subtypes are present at the mouse NMJ and that a resistant component can be identified under 'pharmacological' and/or 'pathological' conditions.

    Baell JB, Forsyth SA, Gable RW, Norton RS, Mulder RJ. (2002) Design and synthesis of type-III mimetics of omega-conotoxin GVIA. J Comput Aided Mol Des 2001 Dec;15(12):1119-36 Biomolecular Research Institute, Parkville, Victoria, Australia.

    Abstract:Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. Our approach involves interactive design of conformationally defined molecular scaffolds that project certain functional groups in a way that mimics the projection of important binding residues as determined in the parent structure. These design principles are discussed and applied to the structurally defined polypeptide, omega-conotoxin GVIA, which blocks voltage-gated, neuronal N-type calcium channels. These ion channels represent therapeutic targets for the development of new analgesics that can treat chronic pain. It is shown how a discontinuous, 3-residue pharmacophore of GVIA can be mimicked by different molecular scaffolds. It is illustrated how such 1st generation leads must necessarily be weak and that optimisability must therefore be built-in during the design process.

    Kohno T, Sasaki T, Kobayashi K, Fainzilber M, Sato K. (2002) Three-dimensional solution structure of the sodium channel agonist/antagonist delta-conotoxin TxVIA.J Biol Chem 2002 Jul 26; [epub ahead of print] Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511.

    Abstract:The three-dimensional solution structure of delta-conotoxin TxVIA, a 27mer peptide agonist/antagonist of sodium channels, was determined by two-dimensional (1)H NMR spectroscopy with simulated annealing calculations. A total of 20 converged structures of delta-conotoxin TxVIA were obtained on the basis of 360 distance constraints obtained from nuclear Overhauser effect connectivities, 28 torsion angle constraints, and 27 constraints associated with hydrogen bonds and disulfide bonds. The atomic root mean square difference about the averaged coordinate positions is 0.35 +- 0.07 angstrom for the backbone atoms (N, Calpha, C) and 0.98 +- 0.14 angstrom for all heavy atoms of the entire peptide. The molecular structure of delta-conotoxin TxVIA is composed of a short triple-stranded antiparallel beta-sheet. The overall beta-sheet topology is +2x, -1, which is the same as those for other conotoxins. However, the three-dimensional structure of delta-conotoxin TxVIA has an unusual hydrophobic patch on one side of the molecule, which may play an important role in the sodium channel binding. These results provide a molecular basis for understanding the mechanism of sodium channel modulation through the toxin-channel interaction and insight into the discrimination of different ion channels.

    Cortez LM, del Canto SG, Testai FD, Biscoglio de Jimenez Bonino MJ. (2002) Conotoxin MI inhibits the alpha-delta acetylcholine binding site of the Torpedo marmorata receptor. Biochem Biophys Res Commun 295:791-795 Departamento de Quimica Biologica, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires (UBA-CONICET), Instituto de Quimica y Fisicoquimica Biologicas, Junin 956, 1113, Buenos Aires, Argentina
    Abstract:The muscle-type nicotinic receptor has two pharmacologically distinguishable acetylcholine binding sites at the alpha-gamma and alpha-delta subunit interfaces; alpha-conotoxins can bind them selectively. As reported, alpha-conotoxin MI has greater affinity for the site near the alpha-delta interface of the BC(3)H1 cell receptor but, in the case of the Torpedo californica receptor, displays greater affinity for that near the alpha-gamma interface. To further investigate ligand selectivity, we study the conotoxin MI- Torpedo marmorata receptor interaction. In this work, we show the binding of alpha-conotoxin MI to the T. marmorata receptor and the influence of the antagonist alpha-Bungarotoxin and the agonist carbamylcholine on such binding; in addition, and contrasting with the results for the Torpedo californica receptor, we identify the alpha-delta subunit interface as the high affinity binding site. This is the first work describing different characteristics of the interaction between alpha-conotoxin MI and receptors from different species of the same genus.

    Yang X.P. and Chiba S.(2002) Three-dimensional solution structure of the sodium channel agonist/antagonist delta-conotoxin TxVIA. Jpn J Pharmacol 89:188-191 Department of Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.

    Abstract:Isolated dog splenic arteries were perfused with Krebs-Henseleit solution at 37 degrees C, using the cannula inserting method. Periarterial nerve electrical stimulation (10-V amplitude; 1-ms duration; 30-s trains of pulses; 1, 4 and 10 Hz) readily caused double peaked vasoconstrictions, i.e., 1st peaked response was mostly inhibited by alpha,beta-methylene ATP and the 2nd one, by prazosin. These responses were consistently inhibited by omega-conotoxin GVIA (omega-CTX), whereas they were facilitated by BIIE 0246, a neuropeptide Y (NPY) Y2-receptor antagonist. The omega-CTX-induced blocking effects of transmitter release were significantly antagonized by BIIE 0246. It is possible that the NPY Y2 receptor activity may partially be l inked to presynaptic Ca2+ channels.

    McIntosh JM, Dowell C, Watkins M, Garrett JE, Yoshikami D, Olivera BM. (2002) alpha-Conotoxin GIC from Conus geographus, a novel peptide antagonist of nAChRs. J Biol Chem 2002 Jul 11; [epub ahead of print] Departments of Psychiatry and Biology, University of Utah, Salt Lake City, UT 84112.

    Abstract:Many venomous organisms produce toxins that disrupt neuromuscular communication in order to paralyze their prey. One common class of such toxins are nicotinic acetylcholine receptor antagonists. Thus, most toxins that act on nAChRs are targeted to the neuromuscular subtype. The toxin characterized in this report, alpha-conotoxin GIC, is a most striking exception. The 16-amino-acid peptide was identified from a genomic DNA clone from Conus geographus. The predicted mature toxin was synthesized and synthetic toxin was used in all studies described. alpha-Conotoxin GIC shows no paralytic activity in fish or mice; furthermore, even at concentrations up to 100 uM, the peptide has no detectable effect on the human muscle nicotinic receptor subtype heterologously expressed in Xenopus oocytes. In contrast, the toxin has high affinity (IC(50) ~ 1.1 nM) for the human alpha3beta2 subunit combination, making it the most neuronal-selective nicotinic antagonist characterized so far. Although alpha-conotoxin GIC shares some sequence similarity with alpha-conotoxin MII, which is also a potent alpha3beta2 nicotinic antagonist, it is much less hydrophobic, and the kinetics of channel block are substantially different. It is noteworthy that the nicotinic ligands in Conus geographus venom fit an emerging pattern in venomous predators with one nicotinic antagonist targeted to the muscle subtype (thereby causing paralysis), and a second nicotinic antagonist targeted to the alpha3beta2 nAChR subtype (possibly inhibiting the fight-or-flight response).

    Toselli M, Masetto S, Rossi P, Taglietti V. (2002) Characterization of a Voltage-dependent Calcium Current in the Human Neuroblastoma Cell Line SH-SY5Y During Differentiation. Eur J Neurosci 3(6):514-522 Istituto di Fisiologia Generale, Universita' di Pavia, Via Forlanini 6, I-27100 Pavia, Italy.

    Abstract:In the presence of retinoic acid, cultured human neuroblastoma SH-SY5Y cells grow processes indicative of neuronal differentiation. A voltage-gated Ca current is already present in undifferentiated cells. A gradual increase of the Ca current density occurs during cell differentiation. According to kinetic and pharmacological properties, Ca currents in differentiated cells are indistinguishable from those elicitable in undifferentiated cells and resemble features of the high-voltage activated currents present in mammalian neuronal cells. omega-conotoxin strongly depresses high-voltage activated currents, both in undifferentiated and in differentiated SH-SY5Y cells. Interestingly, the Ca agonist Bay K 8644 is effective, albeit with great variability from cell to cell, only in differentiated cells and only when barium is the current carrier through the Ca channels. A diversity of high-voltage activated Ca channels of distinct pharmacology has been recently observed in other kinds of neurons. This requires a redefinition of the role that voltage-dependent Ca channel subtypes can play in mammalian neurons.

3 August, 2002

    Conotoxin papers at Cairns I.S.T. Toxinology Meeting:
    The following 10 conotoxin-related presentations were presented at the International Society for Toxinology, 6th Asia-Pacific Congress on Animal, Plant and Microbial Toxins, Cairns, Australia, July 8-12, 2002.
    • Olivera, B.M. (2002) "Conotoxins and cone snails: Evolving a successful neuropharmacological strategy" Symposium 18 - Paper 2, p. 80.
    • Cruz, L.J., Lirazan, C.B., Jimenez, E.C., Craig, A.G. and Olivera, B.M. (2002) "Analogues of endogenous neuropeptides in Conus venoms" Symposium 18 - Paper 3, p. 81.
    • Alewood, P. (2002) "Discovery of analgesic conotoxins" Symposium 18 - Paper 5, p.83
    • Jimenez, E.C., Walker, C., Donevan, S., White, H.S., Zhou, L., Cruz, L.J. and Olivera, B.M. (2002) "Conantokin-L, a new NMDA receptor antagonist from Conus lynceus". Symposium 19 - Paper 1, p. 84.
    • Sandall, D.W., Satkunanathan, N., Bingham, J-P., Moczydlowski, E., Down, J.G., Livett, B.G. and Gayler, K.R. (2002) "alpha-Conotoxins from Conus anemone". Symposium 19 - Paper 2, p. 85.
    • Hawgood, B.J. (2001) "Aspects of the work of Dr. Robert Endean (1925-1997): Australian Marine Biologist and Toxinologist". Symposium 20 - Paper 1, p.89.
    • Mebs, D., Kauferstein, S. and Tytgat, J. (2002) "A structurally conserved K+-channel blocking peptide in different Conus venoms". Symposium 20 - Paper 2, p.89.
    • Lewis, R.J., Nielsen, K.J., Watson, M., Adams, D.J., Hammarstrom, A.K., Gage, P.W., Hill, J.M., Craik, D.J., Thomas, L., Adams, D. and Alewood, P.F. (2002) "Solution structure of a m-conotoxin PIIIA, a preferential inhibitor of persistent TTX-sensitive sodium channels". Symposium 20 - Paper 6, p.94.
    • Raybaudi Massilia, G., Grolleau, F., Schinina, M.E., Barbier, J., Bournaud, R., Molgo, J., Ascenzi, P and Polticelli, F. (2002) "Conopeptides from the venom of the mediterranean worm hunting Conus ventricosus: Biochemical, structural and functional characterisation of contryphan-VN". Poster 2-30, p.171.

2 August, 2002

    Ziconotide Review:
    This review of omega-conotoxin MVIIA (SNX-111, Ziconotide, Prialt) actions by Yong-Xiang Wang and S. Scott Bowersox (2000) is entitled "Analgesic Properties of Ziconotide, a Selective Blocker of N-Type Neuronal Calcium Channels", CNS Drug Reviews 6: (1) 1-21. It may be a few years "old" but it is authored by two of the pioneers in the field of analgesic conopeptide research and is well worth reading - if somewhat difficult to obtain.

    Abstract: Ziconotide is the synthetic equivalent of omega-conotoxin MVIIA, a 25-amino-acid poly-basic peptide found in the venom of the marine snail Conus magus. It is a selective, potent, and reversible blocker of N-type Voltage-Sensitive Calcium Channels (VSCCs). By blocking calcium influx through neuronal N-type VSCCs, ziconotide influences a variety of intracellular calcium-dependent processes including the release of neurotransmitters and the modulation of neuronal excitability. N-type VSCCs are found in high abundance in the superficial Rexed laminae (I and II) of the spinal dorsal horn region innervated by small myelinated and unmyelinated nociceptive afferents from the dorsal roots. In vitro and in vivo results suggest that, when administered intrathecally, ziconotide produces analgesia by blocking neurotransmitter release from primary nociceptive afferents terminating in the superficial layers of the spinal cord dorsal horn.
    Spinal ziconotide produces analgesia in a variety of animal pain models. When delivered intrathecally or epidurally, ziconotide blocks experimentally induced neuropathic, inflammatory, incisional pain, and other pain states that involve central (spinal) sensiti-zation. Ziconotide alleviates allodynia, both primary and secondary hyperalgesia, and pain induced by mechanical, thermal, and noxious chemical stimuli. Clinical investigations have demonstrated that intrathecal and epidural ziconotide produces analgesia in patients suffering from intractable neuropathic pain, cancer, and postoperative pain. At therapeutic doses, intrathecal ziconotide does not produce sedation or suppress systemic blood pressure and heart rate, respiration, or gastrointestinal motility. In vitro and in vivo results also predict that intrathecal ziconotide is not likely to be a drug of abuse.

    Intrathecal Ziconotide and morphine produce additive analgesic effects:
    Wang YX, Gao D, Pettus M, Phillips C, Bowersox SS (2000). Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats. Pain 84: 271-281.

    Abstract: Ziconotide is a selective, potent and reversible blocker of neuronal N-type voltage-sensitive calcium channels (VSCCs). Morphine is an agonist of mu-opioid receptors and inhibits N-type VSCC channels via a G-protein coupling mechanism. Both agents are antinociceptive when they are administered intrathecally (spinally). The present study investigated the acute and chronic (7-day) interactions of intrathecally administered ziconotide and morphine on nociception in several animal models of pain. In the acute study, intrathecal bolus injections of morphine and ziconotide alone produced dose-dependent inhibition of formalin-induced tonic flinch responses and withdrawal responses to paw pressure. The combination of ziconotide and morphine produced an additive inhibition of formalin-induced tonic flinch responses and a significant leftward shift of the morphine dose-response curve in the paw pressure test. After chronic (7-day) intrathecal infusion, ziconotide enhanced morphine analgesia in the formalin test. In contrast, chronic intrathecal morphine infusion produced tolerance to analgesia, but did not affect ziconotide antinociception. Antinociception produced by ziconotide alone was the same as that observed when the compound was co-administered with morphine to morphine-tolerant rats. In the hot-plate and tail immersion tests, chronic intrathecal infusion of morphine lead to rapid tolerance whereas ziconotide produced sustained analgesia with no loss of potency throughout the infusion period. Although ziconotide in combination with morphine produced an apparent synergistic analgesic effects during the initial phase of continuous infusion, it did not prevent morphine tolerance to analgesia. These results demonstrate that (1) acute intrathecal administrations of ziconotide and morphine produce additive or synergistic analgesic effects; (2) chronic intrathecal morphine infusion results in tolerance to analgesia but does not produce cross-tolerance to ziconotide; (3) chronic intrathecal ziconotide administration produces neither tolerance nor cross-tolerance to morphine analgesia; (4) intrathecal ziconotide does not prevent or reverse morphine tolerance.

    Clinical Applications and Experience with Ziconotide:
    While producing outstanding success in treating pain in some patients (see Wang, X. and Bowersox, S. 2000; Staats et al 2001; Leong et al 2001; Webster et al 2001b; see also Oceans of Hope by Linda Marsa) it should be noted, however, that ziconotide has produced adverse side-effects in some other patients (Penn and Paice, 2000; Levin et al 2002). Adverse events reported with ziconotide (Staats et al 2000) are largely neurologic and include tunnel vision, delirium, confusion, slowed thinking, word-finding difficulties, difficulty concentrating, psychosis, hallucinations, gait abnormality, nystagmus, dizziness, amnesia, headache, somnolence, urinary retention, constipation, nausea and vomiting, postural hypotension, and fever. Of note, abnormal gait, dizziness, nystagmus and somnolence tend to peak in the first 14 days of therapy, but confusion and amnesia may peak relatively late, after 90 days (see Webster et al, 2001a; Levin et al, 2002). The FDA has requested a repeat of Stage III clinical trials of ziconotide (since re-badged Prialt) for cancer pain. These studies are currently underway. The FDA has agreed that the drug may be made available to patients for compassionate purposes. Elan has resolved all other pre-clinical issues with the FDA and is committed to bringing this drug to market at the earliest possible opportunity. Prialt is quoted as being 50 times more potent than morphine (see "Oceans of Hope" article by Linda Marsa, 2002) and lacks the side-effects of tolerance seen with the opioids. It is expected that Prialt's use initially will be limited to patients with intractable pain, from cancer, AIDS or severe back problems, because the drug must be administered by catheter directly into the spinal fluid, using a surgically-implantable minipump.

    References:
    Clinical Applications of ziconotide:
    (A) Pain:

    • Bowersox, S., Singh, T., Luther, R.R. (1996) Selective N-type neuronal voltage -sensitive calcium channel bloder, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain. Journal of Pharmacological Experimental Therapeutics 279: 1243-1249.
    • Bowersox, S., Mandema, J., Tarczy-Honoch, K., Miljanich, G., Luther, R.R. (1997) Pharmacokinectics of SNX-111, a selective N-type calcium channel blocker, in rats and cynomolgus monkeys Drug Metab. Dispos. 25: 379-383.
    • Leong, M.S., Webster, L.R., Ellis, D and Gaeta, R.R. (2001) Identification of an Effective and Well-Tolerated Dose Range for Ziconotide, a Novel non-Opioid Analgesic for Chronic Pain". ASCO Abstract #1550-2001
    • Penn, R.D. and Paice, J.A. (2000) Adverse effects associated with the intrathecal administration of ziconotide. Pain 85: 291-296.
    • Staats, P., Charapata, S., Royal, M. et al (2000) Safety profile of intrathecal ziconotide: a new non-opoioid analgesic. Poster Abstract, 19th Annual Scientific Meeting, American Pain Society, No 2-5, 2000, Atlanta, GA.
    • Staats, P.S., Luthardt, F., Shipley, J., Jackson, C. and Fischer, K. (2001) Long-Term Intrathecal Ziconotide Therapy: A Case Study and Discussion. Neuromodulation, 4: 121-126.
    • Webster, L., Henderson, R., Katz, N. and Ellis, D. (2001a) Characterization of Confusion, An Adverse Event Associated with Intrathecal Ziconotide Infusion in Chronic Pain Patients. Pain Medicine 2: 253-254.
    • Webster, L., Gaeta, R.R., Leong, M.S. and Ellis, D. (2001b) Ziconotide Efficacy in Patients with Chronic Intractable Pain of Malignant Origin: Efficacy as a Function of Patient Characteristics." ASCO Abstract #1550-2001.
    • Levin, T., Petrides, G., Wiener, J., Saravay, S., Multz, A.S. and Bailine, S.(2002) Intractable Delirium Associated with Ziconotide Successfully Treated With Electroconvulsive Therapy. Psychosomatics 43: 1, 63-66.

    (B) Stroke:
    • Zhao, Q., Smith, M.L., and Siesjo, B.K. (1994) The omega-conopeptide SNX-111, an N-type calcium channel blocker, dramatically ameliorates brain damage due to trnasient focal ischaemeia. Acta Physiol Scand. 150: 459-461.

    Reviews:
    • Bowersox, S. et al (1998) "SNX-111". Drugs Fut 23 (2): 152-
    • Heading, C. (1999) Ziconotide, Neurex Corp. Current Opinion in CPNS Investigational Drugs.
    • Wang, X. and Bowersox, S. (2000) Analgesic Properties of Ziconotide, a Selective Blocker of N-Type Neuronal Calcium Channels, CNS Drug Reviews 6: (1) 1-21.
    • Shen, G.S., Layer, R.T., McCabe, R.T. (2000) Conopeptides : From deadly venoms to novel therapeutics. Drug Discovery Today 5: 98-106.
    • Jones, R.M. and Bulaj, G. (2000) Conotoxins- new vistas for peptide therapeutics. Current Pharmaceutical Design (Curr Pharm Des) 6: 1249-1285.
    • Jain, K.K. (2000) An evaluation of intrathecal ziconotide for the treatment of chronic pain. Expert Opin Investig Drugs 9: 2403-2410.

7 July, 2002

    Florida Cones:
    Harry Lee's checklist of "The Marine Shells of Northeast Florida" has been revised and updated. This includes the addition of six entries (species number increased from 788 to 794) and revision of taxonomy. The checklist, one of four maintained by Harry, can be found at www.jaxshells.org/marine.htm. This checklist contains 12 species of Conus (#619-630) including images of the following eight species: Conus amphiurgus Dall, 1889a Julia's Cone; Conus anabathrum Crosse, 1865 Florida Cone; Conus burryae Clench, 1942 Mrs. Burry's; Cone Conus daucus Hwass, 1792 Carrot Cone; Conus delessertii Récluz, 1843 Sozon's Cone; Conus ermineus Born, 1778 Agate Cone ; Conus flavescens G. B. Sowerby II, 1834 Flame Conen; Conus stearnsii Conrad, 1869 Dusky Cone; Conus mus Hwass, 1792 Mouse Cone; Conus largilliertii Kiener, 1845 Philippi’s Cone; Conus spurius atlanticus Clench, 1942 Alphabet Cone; and Conus stimpsoni Dall, 1902 Yellow Cone.

2 July, 2002

    Juvenile Conus leopardus:
    Keith Zelinger has contributed an interesting article on juvenile Conus leopardus (Röding, 1798) to Hawaiian Shell News. Included are photos of a 10.5 mm live juvenile shell, and for comparison, a live 64 mm adult specimen showing the foot, siphon and tentacles.

    Conus swainsoni from New Caledonia:
    Claude Berthault and Roger Jeanpierre have contributed some very nice images of Conus swainsoni Estival & Von Cosel, 1986 from their recent finds in New Caledonia to the Hawaiian Shell News.

23 June, 2002

    A spider toxin recognizes omega-conotoxin binding sites:
    Dos Santos, R.G., Van Renterghem, C., Martin Moutot, N. Mansuelle, P., Cordeiro, M.N., Diniz, C.R., Mori, Y., De Lima, M.E. and Seagar, M. (2002) Phoneutria nigriventer omega-phonetoxin IIA blocks the Cav2 family of calcium channels and interacts with omega-conotoxin-binding sites. J Biol Chem 277: 13856-13862
    Abstract:omega-Phonetoxin IIA (omegaPtxIIA), a peptide from spider venom (Phoneutria nigriventer), inhibits high threshold voltage-dependent calcium currents in neurons. To define its pharmacological specificity, we have used patch-clamp methods in cell lines expressing recombinant Ca(v)2.1, Ca(v)2.2, and Ca(v)2.3 channels (P/Q-, N-, and R-type currents, respectively). Calcium currents generated by Ca(v)2.1 and Ca(v)2.2 were blocked almost irreversibly by 3 nm omegaPtxIIA, whereas Ca(v)2.3 showed partial and readily reversible inhibition. Binding assays with mono[(125)I]iodo-omegaPtxIIA indicated that membranes expressing recombinant Ca(v)2.1 or Ca(v)2.2 channels showed a single class of sites with similar affinity (K(D) approximately 50 pm), whereas low affinity interactions were detectable with Ca(v)2.3. Kinetic, saturation, and displacement assays demonstrated that rat brain synaptosomes displayed multiple classes of binding sites for (125)I-omegaPtxIIA. High affinity binding of (125)I-omegaPtxIIA was totally displaced by omegaPtxIIA (K(i) = 100 pm), but only partially by omega-conotoxin GVIA (25% inhibition) and omega-conotoxin MVIIC (50% inhibition at 0.3 microm). (125)I-omegaPtxIIA thus defines a unique high affinity binding site that is predominantly associated with Ca(v)2.1 or Ca(v)2.2 channels.

23 June, 2002

10 May, 2002

7 May, 2002

    Conus textile - among others !:
    Bruno Mathé has a new page to display his collection of Conus textiles from Hawaii, Ile Maurice, Madagascar, The Philippines, and Zanzibar . Click here to view. You need "Java on" option on your browser to enlarge the pictures. Bruno now has 197 images of different species of Conus on his site www.zonatus.com. The new ones are better quality than the older ones (both sides, better precision, etc.). For the recent additions, check out "Quoi de neuf" (What's New)

5 May, 2002

    Calcium channel w-Conotoxins GVIA and MVIIC:
    McDonough SI, Boland LM, Mintz IM, Bean BP (2002) Interactions among toxins that inhibit N-type and P-type calcium channels. J Gen Physiol 119:313-328.
    Abstract A number of peptide toxins from venoms of spiders and cone snails are high affinity ligands for voltage-gated calcium channels and are useful tools for studying calcium channel function and structure. Using whole-cell recordings from rat sympathetic ganglion and cerebellar Purkinje neurons, we studied toxins that target neuronal N-type (Ca(V)2.2) and P-type (Ca(V)2.1) calcium channels. We asked whether different toxins targeting the same channels bind to the same or different sites on the channel. Five toxins (omega-conotoxin-GVIA, omega-conotoxin MVIIC, omega-agatoxin-IIIA, omega-grammotoxin-SIA, and omega-agatoxin-IVA) were applied in pairwise combinations to either N- or P-type channels. Differences in the characteristics of inhibition, including voltage dependence, reversal kinetics, and fractional inhibition of current, were used to detect additive or mutually occlusive effects of toxins. Results suggest at least two distinct toxin binding sites on the N-type channel and three on the P-type channel. On N-type channels, results are consistent with blockade of the channel pore by omega-CgTx-GVIA, omega-Aga-IIIA, and omega-CTx-MVIIC, whereas grammotoxin likely binds to a separate region coupled to channel gating. omega-Aga-IIIA produces partial channel block by decreasing single-channel conductance. On P-type channels, omega-CTx-MVIIC and omega-Aga-IIIA both likely bind near the mouth of the pore. omega-Aga-IVA and grammotoxin each bind to distinct regions associated with channel gating that do not overlap with the binding region of pore blockers. For both N- and P-type channels, omega-CTx-MVIIC binding produces complete channel block, but is prevented by previous partial channel block by omega-Aga-IIIA, suggesting that omega-CTx-MVIIC binds closer to the external mouth of the pore than does omega-Aga-IIIA.

    alpha7 nicotinic receptors localized on glutamate terminals:
    Marchi M, Risso F, Viola C, Cavazzani P, and Raiteri M (2002) Direct evidence that release-stimulating alpha7* nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals. J Neurochem 80(6):1071-1078
    Abstract The existence on glutamatergic nerve endings of nicotinic acetylcholine receptors (nAChRs) mediating enhancement of glutamate release has often been suggested but not demonstrated directly. Here, we study the effects of nAChR agonists on [3 H]-d-aspartate ([3 H]-d-ASP) release from synaptosomes superfused in conditions known to prevent indirect effects. Nicotinic receptor agonists, while unable to modify the basal [3 H]-d-ASP release from human neocortex or rat striatal synaptosomes, enhanced the Ca2+ -dependent exocytotic release evoked by K+ (12 mm) depolarization. Their rank order of potency were anatoxin-a > epibatidine > nicotine > ACh (+ atropine). The anatoxin-a effect, both in human and rat synaptosomes, was antagonized by mecamylamine, alpha-bungarotoxin or methyllycaconitine. The basal release of [3 H]ACh from human cortical synaptosomes was increased by (-)-nicotine (EC50 = 1.16 +/- 0.33 microm) or by ACh plus atropine (EC50 = 2.0 +/- 0.04 microm). The effect of ACh plus atropine was insensitive to alpha-bungarotoxin, methyllycaconitine or alpha-conotoxin MII, whereas it was totally antagonized by mecamylamine or dihydro-beta-erythroidine. To conclude, glutamatergic axon terminals in human neocortex and in rat striatum possess alpha7* nicotinic heteroreceptors mediating enhancement of glutamate release. Release-enhancing cholinergic autoreceptors in human neocortex are nAChRs with a pharmacological profile compatible with the alpha4beta2 subunit combination.

26 April, 2002

24 April, 2002

    Origin of diversity in Conus:
    Duda, TF Jr(1)*, Kohn, AJ.(2) and Palumbi(1) SR. (2001) Origins of diverse feeding ecologies within Conus, a genus of venomous marine gastropods. Biological Journal of the Linnean Society (2001), 73: 391 - 409.
    (1)Department of Organismic and Evolutionary Biology, Biological Laboratories,Harvard University,USA, and (2) Department of Zoology, University of Washington, Seattle, USA

    Abstract: Specialized predators on polychaetes, fishes, hemichordates or other molluscs, members of the predominantly tropical gastropod genus Conus diversified rapidly during the Miocene to constitute the most species-rich modern marine genus. We used DNA sequence data from mitochondrial and nuclear loci of 76 Conus species to generate species-level phylogenetic hypotheses for this genus and then mapped known diets onto the phylogenies to elucidate the origins and evolutionary histories of different feeding specializations. The results indicate that dramatically new feeding modes arose only a few times, that the most derived feeding modes likely arose in the Miocene, and that much of the known diversity of Conus that was generated during Miocene radiations has survived to the present. . 2001 The Linnean Society of London
    ADDITIONAL KEYWORDS:Gastropoda Conus molecular phylogeny feeding ecology ecological diversification.

    Student project on Venoms:
    Alison Heggie and seven other medical students at Edinburgh University, UK, have been studying Venoms and venomous animals for 4 weeks, including cone snails, and have provided a very nice presentation in this web project. Their aims were :

    • to thoroughly investigate some of the venomous creatures of clinical significance to humans.
    • to research the mechanism of venoms and their clinical effects.
    • to discuss the management and care of an envenomated patient.

    • - and concurrently,
    • to improve their evidence based learning and website designing skills, and
    • to develop their teamwork and time-management abilities.
    Take a look. The project is nearing completion. I think you will agree with me that they have achieved those goals admirably.

18 April, 2002

    Front-end of a Conus striatus:
    Jeff's Nudibranch and Coral Reef Gallery has this very confronting photo of the front -end of a Conus striatus, and links to another live Conus.

16 April, 2002

    An "Internet Interview" with Bruce Livett:
    Eduardo Moreira from the Brazil Shell Club "interviewed" Bruce Livett in February 2001 about his scientific work with cone shells and conotoxins and his interaction with other malacologists and shell collectors. This extensive Intervista web "interview" for Callostoma was subsequently published (in condensed version) in American Conchologist Volume 30, Number 1, 2002, pp. 5 & 14.

13 April, 2002

21 March, 2002

20 March, 2002

    Snack attack !:
    David Toitou has an amazing collection of images of a Conus cedonulli attacking and consuming a fire worm (Hermodice carunculata).

    Some Conus beauties !: Guido Poppe has some exceptional cones on display, including the following new additions to his list :
    Conus gubernator Hwass in Bruguière, 1792, Mozambique. Only a few specimen with these exquisite patterns are found among the hundreds fished each year. Size: 60 mm. Quality: GEM ; Conus hopwoodi Tomlin, 1936, Philippines ; Wonderful dark specimen of one of my very preferred Conus because of the elegant shape and nice silk appearance. It lives from Melanesia and the Solomons north to the China Sea. Said to be shallow water species, but this one was taken by tangle nets. Most shells are grey with sparse brown flecking: this one has a dominant chocolate colour. Size: 28 mm. Quality: GEM. Conus kinoshitai Kuroda, 1956. This piece created quite some excitement among the Philippine fisherman, as for long there were no pure lemon yellow kinoshitai available. The specimen is preserved with its perfect periostracum, forming a corona on the shoulder. Size: 60 mm. Quality: Gem, With operculum; Conus pictus Reeve, 1843 South Africa. This is among the most beautiful that this outstanding species has to offer. Taken alive. The yellow band on the shoulder combined with the brown spotting and the alernating white spiral bands is rare. Size: 35,8 mm. Quality: GEM, with operculum; Conus pictus Reeve, 1843. South Africa. A dead collected fabulous pictus in gem condition, and with fabulous colours. One of the most beautiful ever found. Size: 32,3 mm. Quality: GEM. This is among the most beautiful that this outstanding species has to offer. Taken alive. The yellow band on the shoulder combined with the brown spotting and the alernating white spiral bands is rare. Size: 35,8 mm. Quality: GEM, with operculum; Conus pulcher Lightfoot, 1786. Togo. Generally known as the biggest among CONIDAE shells. Shells exceeding 180 mm are very uncommon. The shells from Togo belong to the typical very slender C. pulcher s. s.. More northern populations are broader (C. pulcher prometheus, Senegal) or very broad (C. pulcher siamensis, Canaries). Size: 189 mm. Quality : Definitely in the FINE range, considering the size of the specimen. With periostracum; Conus pulcher Lightfoot, 1786. Togo. Generally known as the biggest among CONIDAE shells. Shells exceeding 180 mm are very uncommon. The shells from Togo belong to the typical very slender C. pulcher s. s.. More northern populations are broader (C. pulcher prometheus, Senegal) or very broad (C. pulcher siamensis, Canaries). Size: 182 mm. Quality : Definitely in the FINE range, considering the size of the specimen. With periostracum ; Conus sp Philippines. A very curious deep water Conus from the central Philippines which resembles RKK, Plate 54 fig. 12, but which is definitely another species. On Mactan this Conus is occasionally sold as C. cebugensis, the little brother of C. excelsus. Indeed, its spire is much higher than in usual acutangulus. Natural defect on lower lip and small growth defects. Best one out of half a dozen that we could view. Size: 32 mm. Quality: Natural defect on lower lip and small growth defects. Fine++ ; Conus vexillum Gmelin, 1791. Philippines: Piece with a fabulous white band on its centre. For aesthetic collections. Better than usual quality for vexillum. Size: 86 mm. Quality: Very nice for the species. Spire slightly eroded as always. Microdefects on the not filed lip. Close to gem. ; Conus zapatoensis Röckel, 1987, Philippines: Described from Negros, not so long ago, and later discovered on Bantayan Island, not so far away. Now from Balicasag !! While small shells are occasionally available, the real large thing as the one shown here remains rare. Size: 47 mm. Quality: GEM. - and another Size: 43 mm. Quality: GEM and another, Size: 43 mm. Quality: GEM.

11 March, 2002

9 March, 2002

    Conopeptide References - updated:
    The following recent references to work on conopeptides (conotoxins, conantokins, conophysins, contulakins, conorfamide, etc) have come to my notice :
  • Bandyopadhyay PK, Garrett JE, Shetty RP, Keate T, Walker CS, Olivera BM(2002) From the Cover: gamma -Glutamyl carboxylation: An extracellular posttranslational modification that antedates the divergence of molluscs, arthropods, and chordates.Proc Natl Acad Sci U S A. 99:1264-1269.
  • Kato A, Ohkubo T, Kitamura K. (2002) Algogen-specific pain processing in mouse spinal cord: differential involvement of voltage-dependent Ca(2+) channels in synaptic transmission. Br J Pharmacol. 135:1336-1342.
  • Price-Carter M, Bulaj G, Goldenberg DP. (2002) Initial Disulfide Formation Steps in the Folding of an omega-Conotoxin. Biochemistry. 41:3507-3519.
  • Ridley DL, Pakkanen J, Wonnacott S. (2002) Effects of chronic drug treatments on increases in intracellular calcium mediated by nicotinic acetylcholine receptors in SH-SY5Y cells. Br J Pharmacol. 135:1051-1059.
  • Staras K, Gyori J, Kemenes G. (2002) Voltage-gated ionic currents in an identified modulatory cell type controlling molluscan feeding. Eur J Neurosci. 15:109-119.
  • Champtiaux N, Han ZY, Bessis A, Rossi FM, Zoli M, Marubio L, McIntosh JM, Changeux JP. (2002) Distribution and pharmacology of alpha 6-containing nicotinic acetylcholine receptors analyzed with mutant mice. J Neurosci. 22:1208-1217.
  • Gouvea Dos Santos R, Van Renterghem C, Martin-Moutot N, Mansuelle P, Cordeiro MN, Diniz CR, Mori Y, De Lima ME, Seagar M. (2002) omega Phoneutria nigriventer toxin blocks the Cav2 family of calcium channels and interacts with omega conotoxin binding sites. J Biol Chem. 2002 Feb 4
  • Rathmayer W, Djokaj S, Gaydukov A, Kreissl S. (2002) The neuromuscular junctions of the slow and the fast excitatory axon in the closer of the crab Eriphia spinifrons are endowed with different Ca2+ channel types and allow neuron-specific modulation of transmitter release by two neuropeptides. J Neurosci. 22:708-717.
  • Li RA, Sato K, Kodama K, Kohno T, Xue T, Tomaselli GF, Marban E. (2002) Charge conversion enables quantification of the proximity between a normally-neutral mu-conotoxin (GIIIA) site and the Na+ channel pore. FEBS Lett. 511:159-164.
  • Moran O. (2001) Molecular simulation of the interaction of kappa-conotoxin-PVIIA with the Shaker potassium channel pore. Eur Biophys J. 30:528-536.
  • Yen TY, Yan H, Macher BA. (2002) Characterizing closely spaced, complex disulfide bond patterns in peptides and proteins by liquid chromatography/electrospray ionization tandem mass spectrometry. J Mass Spectrom. 37:15-30.
  • Kitagawa H, Yamazaki T, Akiyama T, Mori H, Sunagawa K. (2001) Effects of ketamine on in vivo cardiac sympathetic nerve endings. J Cardiovasc Pharmacol.38 Suppl 1:S39-42.
  • Nakamura M, Oba Y, Mori T, Sato K, Ishida Y, Matsuda T, Nakamura H. (2002) Generation of polyclonal antibody against mu-conotoxin GIIIA using an immunogen of [Cys(5)]mu-conotoxin GIIIA site-specifically conjugated with bovine serum albumin. Biochem Biophys Res Commun. 2002 290:1037-1041.
  • Hui K, Lipkind G, Fozzard HA, French RJ. (2002) Electrostatic and steric contributions to block of the skeletal muscle sodium channel by mu-conotoxin. J Gen Physiol. 119:45-54.
  • El Ayadi A, Afailal I, Errami M. (2001) Effects of voltage-sensitive calcium channel blockers on extracellular dopamine levels in rat striatum. Metab Brain Dis. 16:121-131.
  • Kaneko S, Cooper CB, Nishioka N, Yamasaki H, Suzuki A, Jarvis SE, Akaike A, Satoh M, Zamponi GW. (2002) Identification and characterization of novel human Ca(v)2.2 (alpha 1B) calcium channel variants lacking the synaptic protein interaction site. J Neurosci.22:82-92.
  • Takahara A, Koganei H, Takeda T, Iwata S. (2002) Antisympathetic and hemodynamic property of a dual L/N-type Ca(2+) channel blocker cilnidipine in rats. Eur J Pharmacol.434 (1-2):43-47.
  • Nirthanan S, Joseph JS, Gopalakrishnakone P, Khoo HE, Cheah LS, Gwee MC (2002) Biochemical and pharmacological characterization of the venom of the black scorpion Heterometrus spinifer. Biochem Pharmacol. 63:49-55.
  • Silver, B, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, Levi R (2002) Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings. Proc Natl Acad Sci U S A.99:501-506.
  • Kulak JM, McIntosh JM, Quik M. (2002) Loss of nicotinic receptors in monkey striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment is due to a decline in alpha-conotoxin MII sites. Mol Pharmacol.61:230-238.
  • Fujita R, Takayama N, Ueda H. (2002) The cognition-enhancer nefiracetam is protective in BDNF-independent neuronal cell death under the serum-free condition. Neurochem Int. 40:139-143.
  • Hirota K, Kudo M, Kudo T, Matsuki A, Lambert DG. (2000) Inhibitory effects of intravenous anaesthetic agents on K+-evoked norepinephrine and dopamine release from rat striatal slices: possible involvement of P/Q-type voltage-sensitive Ca2+ channels. Br J Anaesth. 85:874-880.
  • Massilia GR, Schinina ME, Ascenzi P, Polticelli F. (2001)Contryphan-Vn: a novel peptide from the venom of the Mediterranean snail Conus ventricosus. Biochem Biophys Res Commun.288:908-913
  • Favreau P, Gilles N, Lamthanh H, Bournaud R, Shimahara T, Bouet F, Laboute P, Letourneux Y, Menez A, Molgo J, Le Gall F. (2001) A new omega-conotoxin that targets N-type voltage-sensitive calcium channels with unusual specificity. Biochemistry. 40:14567-14575.

6 March, 2002

    Xenome and Amrad media releases:
    Two Australian companies involved in the development of cone shell venom components for the treatment of pain, announced progress via media releases:
  • Xenome Ltd, announced (25th February 2002) [see Media articles] the commencement of pre-clinical testing of a new molecule [based on chi-conotoxin MrIA/B from Conus marmoreus that targets the neuronal noradrenaline transporter] to treat certain types of pain, for which there is currently a lack of effective treatment. Further, Xenome, announced (6 March 2002) that it has signed an agreement with Ionix Pharmaceuticals Ltd, a European analgesic drug discovery company. The collaboration includes the search for selective antagonists of a sodium channel drug target that is expressed in the Periphipal Nervous System. Xenome and Ionix will collaborate on the design, synthesis and screening of toxins and derivatives for evaluation as potential inhibitors of proprietary Ionix drug targets. Xenome's co-founder and Head of Research, Dr Roger Drinkwater, said: "The molecule has proved to be effective in animals, treating neuropathic and inflammatory pain, with no adverse side effects. Xenome will now commence a series of tests to confirm efficacy and begin studies to define the metabolic processing of the molecule as a part of the preclinical testing program. These will be followed by more formal toxicity studies, as a prelude to testing in humans."
  • Amrad Corp, announced (28 February, 2002) that positive findings from its Phase I/II clinical trial in patients with chronic severe pain have led to early completion of the study, enabling the Company to advance AM336 (based on omega-conotoxin CVID from Conus catus) to the next stage of development additional safety studies and a full Phase II trial to commence during 2002.
  • Cognetix Inc. forms pain management collaboration with Elan
    Related article from the "Archives":5 Feb 2000
    Cognetix, Inc. has completed a licensing and collaboration agreement with Elan Corporation, plc. to develop and commercialize Cognetix's contulakin-G (CGX-1160) for short-term management of post-operative pain using Elan's proprietary MEDIPAD Drug Delivery System.
    CGX-1160 is a conopeptide derived from the venom of the marine snail Conus geographus. It is a neurotensin receptor agonist that has demonstrated efficacy in a wide range of pain models, including acute pain. CGX-1160 appears to be well tolerated, based on pre-clinical assessment, and to have an extended duration of analgesia. Moderate to severe post-operative pain generally is managed with morphine or other opioid analgesics, but these are not without problems relating to side effects and tolerance development.
    Elan's MEDIPAD Drug Delivery System combines the convenience of a transdermal patch with the drug delivery capabilities of an infusion pump. The system is disposable, inexpensive and can be used to infuse drugs over a 24 to 48 hour timeframe. Cognetix and Elan will exclusively license, for specific applications, CGX-1160 and MEDIPAD, respectively, to a Cognetix subsidiary.
    "This is an exciting opportunity for Cognetix on several levels, the strategic partnership will bring together a unique drug/device combination to tackle a treatment area of urgent medical need. We feel that this is a great strategic fit for Cognetix and Elan, especially with CGX-1160, the lead compound in our pain therapeutics portfolio. Elan's experience in drug delivery and their interest in pain management, notably the advancement of ziconotide, is well established. We believe that this deal further validates our technological approach." said Brian Anderson, CEO of Cognetix.
    He continued "In a period of less than 12 months, Cognetix has concluded two major corporate partnerships, with compounds now being advanced to clinical trials. In February 1999 we partnered with Medtronic, Inc. to develop another Cognetix conopeptide, conantokin- G (CON-G), for the treatment of intractable epilepsy."
    The Medtronic agreement calls for the development of CON-G using a SynchroMed infusion system for delivery of the drug into the central nervous system of epilepsy patients. CON-G is expected to enter human trials later this year.

5 March, 2002

    Cone Shell Images:
    ATLANTIC worldwide specimen shells, P.O.Box 4136, 4461-901 Sª Hora, PORTUGAL, have some nice images of cone shells from Angola. Included are:
    Conus albuquerquei Trovão, 1978 +13mm F++/F+++ Rare, now impossible to obtain, Angola 20; Conus bulbus Reeve, 1843 +25mm F++/F+++ Exceptional size, few only, take the chance, Angola 18; Conus chytreus Tryon, 1883 +25mm F++/F+++ Rare, true one's, very few, Angola 25; Conus fuscolineatus Sowerby, 1905 +25mm F++/GEM Rare, top class shells, for specialist, Angola 30; Conus nobrei Trovão, 1975 +14mm F++/F+++ Rare, only these, for specialist, Angola 20; Conus zebroidesKiener, 1849 +30mm F+++ Rare, exceptional quality, very fresh, Angola.

23 February 2002

22 February 2002

21 February 2002

    Oceans of Hope - Prialt and more !!:
    Greg Bulaj (Cognetix) brought the following interesting article in Los Angeles Times to my attention : Oceans of Hope by Linda Marsa, Times Staff Writer [available for archive purchase].
    Extract: "The new pain treatment, called Prialt, is the first in a wave of marine-based medicines expected to reach pharmacy shelves during the next few years. ... Scientists are hopeful that these marine drugs may prove more effective than some current therapies. Scientists say Prialt (whose generic name is ziconotide), for instance, the pain remedy derived from cone snails, will revolutionize the treatment of severe, chronic pain because the targeted therapy doesn't have the unpleasant side-effects of morphine or other opiates -- it's not habit-forming and it doesn't envelop users in a narcotic fog."
    "Its quite exciting because this treats pain conditions that haven't responded to conventional therapy," said Dr. Michael S. Leong, an assistant professor at the Stanford University School of Medicine, who tested Prialt on 108 patients with cancer and AIDS. "All of these patients had exhausted everything that was available, and even the worst patients with intractable pain got some relief." etc..... (see original article, link above).

    Dublin, Ireland, February 4, 2002 -- Elan Corporation, plc (NYSE: ELN):
    With respect to PrialtTM, Elan has reached an agreement with the US Food and Drug Administration ("FDA") through which this novel and important compound may be introduced to the US market. To optimise the label Elan has agreed to conduct one additional Phase III study which will be initiated in the second quarter. The FDA has agreed that the drug may be made available to patients for compassionate purposes. Elan has resolved all other pre-clinical issues with the FDA and is committed to bringing this drug to market at the earliest possible opportunity.

    Hard to keep up with all these name changes ! First it was Conotoxin MVIIA, then SNX-111 and CI 1009, then Ziconotide, now Prialt(TM). Let's hope these repeat Stage III clinical trials turn up trumps.BGL

9 February 2002

7 February 2002

    Long-term Ziconotide therapy:
    Peter S. Staats, MD, Frederick Luthardt, MA Jane Shipley, BA Catherine Jackson, RN, BSN Karl Fischer, RN (2001) Long-Term Intrathecal Ziconotide Therapy: A Case Study and Discussion. Neuromodulation, 4: 121-126.

    Abstract: This case study describes the therapeutic result of intrathecal administration of ziconotide, a new synthetic neurotoxin derived from the venom of the Philippine marine snail, Conus magus, to a 48-year-old male with chronic, and previously untreatable, neuropathic pain of an undeterminable etiology. The patient suffered tactile allodynia and reported his baseline pain intensity to be 80 mm on the 100 mm Visual Analog Scale for Pain Intensity. After responding affirmatively to treatment in a blinded placebo-controlled trial, the patient enrolled in a long-term, open-label trial. Currently, the patient rates his pain at 16 mm and enjoys an improved quality of life. This result suggests that treatment with ziconotide may provide outstanding relief to patients with chronic pain while sparing them the unpleasant side effects associated with other treatments.

28 January 2002

    Conorfamide: a venom peptide from Conus spurius, 'Alphabet Cone':
    Researchers from the Centro de Neurobiologia, Universidad Nacional Autonoma de Mexico in Juriquilla, Queretaro, Mexico, have teamed up with 'Toto' Olivera to discover a novel Conus peptide, conorfamide, from a worm-eating Atlantic Conus species, Conus spurius Clench, 1942.

    Maillo, M., M.B. Aguilar, E. Lopez-Vera, A.G. Craig, G. Bulaj, B.M. Olivera and E.P. Heimer de la Cortera (2001) Conorfamide, a Conus venom peptide belonging to the RFamide family of neuropeptides. Toxicon, 40: 401-407.
    Abstract: A novel Conus peptide, conorfamide-Sr1, has been characterized. The sequence of the natural peptide was determined using standard Edman sequencing methods and mass spectrometry, and confirmed by chemical synthesis. The peptide has 12 amino acids and no cysteine residues. The following sequence was obtained: GPMGWVPVFYRF-NH(2). No other peptide from a vermivorous Atlantic Conus species has previously been characterized. Conorfamide-Sr1 belongs to the RFamide neuropeptide family, and is the first RFamide peptide to be found in any venom. The presence of conorfamide-Sr1 as a major peptide in Conus spurius venom suggests that Conus lineages in the Atlantic may have evolved novel Conus venom peptide families.

26 January 2002

    Search for Cone Shells:
    You can search for cone shells by geographic location at the Melvill-Tomlin Collection of molluscs at the Museum of Wales Biodiversiry Database Online. To simplify this procedure just click here, scroll down to the "Taxonomic Search Fields" and enter in the data entry box "Current Genus" Conus, and in the "Geographic Search Field" (pull down menu) choose for example Red Sea. This search returned 27 records (some duplicate species). A similar search for the Pacific region returned 427 Conus records. In contrast a search for New Zealand Seas yieled just one (Conus kermadecensis, Iredale, 1913, Sunday Is. Kermadec Islands, NZ). There are lots of options here to search by Status, Taxonomic Search Fields, Location, and Source. Have fun :)

    Review on Analgesic Properties of Ziconotide:
    Two earlier reviews on Ziconotide action are, one by Yong-Xiang Wang and S.Scott Bowersox, Department of Pharmacology, Elan Pharmaceuticals, Menlo Park, CA, USA:

  • Wang, Y.X. and Bowersox, S.S. (2000) "Analgesic Properties of Ziconotide a Selective blocker of N-type neuronal calcium channels".CNS Drug Reviews, 6: 1-20
    Abstract: Ziconotide is the synthetic equivalent of omga-conotoxin MVIIA, a 25-amino-acid polybasic peptide found in the venom of the marine snail Conus magus. It is a selective, potent, and reversible blocker of N-type VSCCs. By blocking calcium influx through neuronal N-type VSCCs, ziconotide influences a variety of intracellular calcium-dependent processes including the release of neurotransmitters and the modulation of neuronal excitability. N-type VSCCs are found in high abundance in the superficial Rexed laminae (I and II) of the spinal dorsal horn region innervated by small myelinated and unmyelinated nociceptive afferents from the dorsal roots. In vitro and in vivo results suggest that, when administered intrathecally, ziconotide produces analgesia by blocking neurotransmitter release from primary nociceptive afferents terminating in the superficial layers of the spinal cord dorsal horn.
    Spinal ziconotide produces analgesia in a variety of animal pain models. When delivered intrathecally or epidurally, ziconotide blocks experimentally induced neuropathic, inflammatory, incisional pain, and other pain states that involve central (spinal) sensitization. Ziconotide alleviates allodynia, both primary and secondary hyperalgesia, and pain induced by mechanical, thermal, and noxious chemical stimuli. Clinical investigations have demonstrated that intrathecal and epidural ziconotide produces analgesia in patients suffering from intractable neuropathic pain, cancer, and postoperative pain.
    At therapeutic doses, intrathecal ziconotide does not produce sedation or suppress systemic blood pressure and heart rate, respiration, or gastrointestinal motility. In vitro and in vivo results also predict that intrathecal ziconotide is not likely to be a drug of abuse. Long-term administration of intrathecal ziconotide does not lead to tolerance nor does it influence morphine analgesia and morphine tolerance to analgesia. Drug interaction studies have shown that additive or synergistic analgesic effects occur, when ziconotide is administered intrathecally together with spinal morphine, clonidine, baclofen, or bupivacaine. Ziconotide is a promising analgesic with novel mechanism of action for the treatment of the patients suffering from opioid-resistant neuropathic and malignant pain.
  • A still earlier account of the actions of SNX-111 (previous name for Ziconotide - a synthetic version of omega conotoxin MVIIA) is the review by Bowersox, S. et al (1998) "SNX-111". Drugs Fut 23 (2): 152 [abstract not listed]

25 January 2002

    Nice Cone Shell Images:
    Guido T. Poppe has some exceptional cone shells on his conchology web site including : Conus colorovariegatus Kosuge, 1981 Philippines. Balicasag Island, near Panglao, Bohol. With tangle nets, 130-230 m deep. October 2001. One of the best specimen ever found: chocolate brown in top quality; . Conus episcopatus da Motta, 1982 Philippines. North Bohol. Calitoban Island. 20-25 m deep by divers. Nighttime. October 2001. A splendid specimen of the Philippine episcopatus, which is rare; Conus orbignyi Audouin, 1831 Philippines. Aliguai Island, near Dipolog, Mindanao, tangle nets 130-230 m deep. October 2001. Out of the bottoms around Aliguai, a set of 3 ALBINO orbignyi. This is one of these. Never seen before. Conus orbignyi Audouin, 1831 Philippines. Aliguai Island, near Dipolog, Mindanao, tangle nets 130-230 m deep. October 2001. Out of the bottoms around Aliguai, a set of 3 ALBINO orbignyi. This is one of these. Never seen before. Size: 35 mm. Quality: GEM, lip slightly filed, normal in this species; and Conus orbignyi Audouin, 1831 Philippines. Aliguai Island, near Dipolog, Mindanao, tangle nets 130-230 m deep. October 2001. Out of the bottoms around Aliguai, a set of 3 ALBINO orbignyi. This is one of these. Never seen before. Size: 42 mm. Quality: GEM.

    Conus mediterraneus Painting:
    Dimitris Mytaras love and passion for seashells is well known in Greece, as are his paintings:
    Mr Mytaras studied painting at the school of fine arts in Athens, and set design at the Ecole des Art decoratifs in Paris. He has held exhibitions in many capital cities around the world and taken part in almost all the important biennial exhibitions. The paintings and text are taken from the book "FORTY GREEK SHELLS" which includes a CD ('THE SOUND OF THE DEEP'). For further information concerning the book email aegeanshells
    Conus mediterraneus: This spear fisher of the Mediterranean sea, will try to swallow its catch whole, opening its proboscis much wider than anyone could suspect. It impales it's poisonous arrow into the unsuspecting victim. Click here to view the collection of cone shells

23 January 2002

    Keeping up with the Cones:
    The American Museum of Natural History has an interest in cone shells:

  • Cones on show Here they have a nice live Conus striatus imaged in their Mollusks exhibit. Note the striated pattern extends to the "skirt". Also depicted is a Conus betulinus (Beech Cone), and a Conus marmoreus, (Marble Cone). Click on any of the small images on the left panel to display a large image of that particular mollusck, or explore the "Spectrum of Life" from the cladogram provided by Dr. Niles Eldredge, curator of invertebrates.

  • The current (February 2002) issue of "Natural History", the 10 issues-a-year magazine of the American Museum of Natural History, has two great articles - one on cone shells and conotoxins, "Keeping Up With the Cones" by Aparna Sreenivasan, and the other on evolution from sea to land and vice-versa, and the importance of incumbency.

      The article on conotoxins has close-ups of the animals, and mention of Cognetix. Some cones seem to adapt their venom to particular prey -- instant evolution (see articles by Duda and Palumbi).

      The other article by Geerat J. Vermeij ("Why Are There No Lobsters on Land or Bats at Sea?") has some fascinating information about evolution from sea to land and vice-versa, and the importance of incumbency (not only in politics). The magazine is addressed to the general public and makes for interesting reading, for instance, feather mites are smarter than you might think.

16 January 2002

13 January 2002

    Cone Shell Bibliography:
    This extensive on-line Conus Bibliography, organized by species, provides a list of key reference books and publications for each species of Conus. Source is Guy Guerrero (former chairman of French Association of Conchology) and webmaster of Malacos.com (France).

    Tropical Cones:

  • Sylvain Le Cochennec of Paris has assembled a number of beautiful Seashells Collected in Tropical Seas among which are his collection of Conus species, many with images. Choose "more conus...", scroll down the left hand panel to "Conidae" and select highlighted Conus species from list to display its image which will appear in the right hand frame.

  • Then there is the Image Gallery of Conidae at Schooner Specimen Shells.

12 January 2002

    South American Cones:

  • Two interesting articles by William R Cargile, one providing a "Description of Conus lenhilli, a new species from the Western Atlantic", and the other a "Description of Conus ignotus, a new species from Nicaragua" are now available on-line from the Femorale articles" web site (both articles extracted from (Siratus, No.14, February, l998, p.9. - ISSN 0103-5606). In the latter article, the features of Conus ignotus Cargile, 1998, discovered from offshore eastern Nicaragua ,is described and compared to the Florida endemic C. binghamae Petuch, 1987; and to C. eversoni Petuch, 1987; and C. patae Abbott, 1971. The type locality of Conus ignotus is west side of Quita Sueño Bank, off the northeastern Honduras coast, and was collected in 25-35m.
  • There is also an article by José Coltro Jr. on "ECUADOR: A NEW ADVENTURE" describing the collection of Conus princeps lineolatus , and other shells.
  • The Femorale Ltd. web site provides a wealth of interesting information and resources for shell collectors. The material is very well organized, allowing searches for shells available for purchase. You can search for a specific shell (or search any partial name of the shell); a family (eg. CONIDAE); or by locality; and look for recent additions to the list. There are interesting links to other sites, and you can even view some members of the Brazilian Shell Club (Conquiliologistas do Brazil), and survey the cover pages of the major shell magazines and publications.
    Take a look at upwards of 2000 shell images of which there are some 300 images of Conus. Enjoy !

11 January 2002

    Hazardous molluscs:
    The venom apparatus of the Superfamily Conacae, family Conidae (Cone Shells), is featured here at the Archerd Shell Collection at Washington State University (together with images of Conus sieboldii, Siebold's Cone, and Conus litteratus, Lettered Cone.

  • The caption of this reconstructed image of a venomous cone shell pulling in its victim for lunch depicts a Conus textile pulling in a small fish for lunch, but Conus textile is a molluscivore and is unlikely to hunt fish.
  • A number of specific Conus species are implicated in injuries to humans. They include in reported descending order of threat Conus geographus, Conus aulicus, Conus gloriamaris, Conus marmoreus, Conus textilis, Conus tulipa, Conus striatus, Conus omaria, Conus catus, Conus obscurus, Conus imperialis, Conus pulicarius, Conus quercinus, Conus litteratus, Conus lividus, Conus sponsalis and Conus magus (Halstead (1978). Source: IV. Injected venoms and toxins - "A detailed overview of marine venoms and toxins, the delivery systems involved and a brief summary of their effects on humans and other animals" .
  • Some brief notes about dangerous Mollusca are also given at this site on hazards in Maltese waters, and at Riparia.org where Mark Anderson, MD has an interesting and informative article on "Poisonous Sea Life" (including Cone Shells).

9 January 2002

    mu-conotoxin GIIIA mechanism of action at muscle sodium channel:
    Hui K, Lipkind G, Fozzard HA and French RJ (2002) Electrostatic and steric contributions to block of the skeletal muscle sodium channel by mu-conotoxin. J Gen Physiol. 119: 45-54.
    Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
    Pore-blocking toxins are valuable probes of ion channels that underlie electrical signaling. To be effective inhibitors, they must show high affinity and specificity and prevent ion conduction. The 22-residue sea snail peptide, mu-conotoxin GIIIA, blocks the skeletal muscle sodium channel completely. Partially blocking peptides, derived by making single or paired amino acid substitutions in mu-conotoxin GIIIA, allow a novel analysis of blocking mechanisms. Replacement of one critical residue (Arg-13) yielded peptides that only partially blocked single-channel current. These derivatives, and others with simultaneous substitution of a second residue, were used to elucidate the structural basis of the toxin's blocking action. The charge at residue-13 was the most striking determinant. A positive charge was necessary, though not sufficient, for complete block. Blocking efficacy increased with increasing residue-13 side chain size, regardless of charge, suggesting a steric contribution to inhibition. Charges grouped on one side of the toxin molecule at positions 2, 12, and 14 had a weaker influence, whereas residue-16, on the opposite face of the toxin, was more influential. Most directly interpreted, the data suggest that one side of the toxin is masked by close apposition to a binding surface on the pore, whereas the other side, bearing Lys-16, is exposed to an aqueous cavity accessible to entering ions. Strong charge-dependent effects emanate from this toxin surface. In the native toxin, Arg-13 probably presents a strategically placed electrostatic barrier rather than effecting a complete steric occlusion of the pore. This differs from other well-described channel inhibitors such as the charybdotoxin family of potassium channel blockers and the sodium channel-blocking guanidinium toxins (tetrodotoxin and saxitoxin), which appear to occlude the narrow part of the pore.

6 January 2002

    Philippines Shells (Live images):
    Emanuel GUILLOT DE SUDUIRAUT has updated his Shells of Philippines site with 3 new Cone Shell species.
    Conus circumcisus (Born 1778), Calituban Is. ; a live Conus aulicus (Linnaeus 1758) Balicasag isl. ; and a live Conus textile (Linnaeus 1758) Balicasag isl.
    The CONIDAE page now contains live images of the the following Conus species: Conus aphrodite ; Conus aulicus ; Conus australis ; Conus bocki ; Conus comatosa ; Conus dayriti ; Conus eugrammatus ; Conus floridulus ; Conus generalis ; Conus gloriamaris ; Conus imperialis ; Conus kimioi ; Conus kintoki ; Conus menmiae ; Conus pertusus ; Conus recluzianus forma roseorapum ; Conus tessulatus ; and Conus textile.

    Conus ateralbus:
    A seemingly innocent question on CONCHL by Carol Brunner, North Miami, FL, seeking information about Conus ateralbus Kiener,1849 (native to Cape Verde) evoked a large response from List members among which was this informative reply from Carlos Afonso (South Portugal):
    'In the book Cone Shells from the Cape Verde Islands: "A difficult puzzle", by Röckel, Rolán & Monteiro (1980), these authors refer to the following: "...The consideration of C. ateralbus Kiener as a valid species has been quite controversial. Lost for many years, despite the extreme accuracy of Kiener's illustrations, it was brought back into the malacological scene by Burnay and Monteiro (1977) as a valid species. Several researchers disagreed,considering C. ateralbus as anything from C. venulatus, Hwass to gerontic C. cuneolus, Reeve !..."
    "...Setting aside the obviously wrong hypothesis, there remained the problem of C. ateralbus Kiener being synonymous with C. venulatus Hwass, as suggested by many. Let us remark right away that the existence of several constant differences between the two would give C. ateralbus at least a sub-specific rank, far more than a mere synonym, provided that geographical separation holded..." Personal observations, for the many specimens of Conus ateralbus collected in Sal Island (Cape Verdes), the colour and pattern variations with in this specie are almost absent. On the other had Conus venulatus, also collected in Sal Island, is extremely variable in colour. Observations by ROLÁN, E. (1991) for Sal Island on the family Conidae and in particular for these two species, match the ones I have encountered recently. This author, in his fabulous work, says. "...variabilidade de dibujo y color es muy escasa..." for C. ateralbus. I think you don't have to be an experienced collector or researcher, to find obvious differences between these two "species" after collecting them and having fair numbers of each one of them. The problem about the Cone species of the Cape Verde is that if you don't collected them by your self (or trade or buy them with full data) it will be very difficult to identify them afterwards. You must know exactly where they came from, from what Bay, what habitat, what depth, etc ..., not just a label saying Sal Island Cape Verdes. This will be a first big step to ID Cones from the Cape Verde Islands. All thought Sal is a small Island you can wander around hunting C. ateralbus for days, weeks and still come up with nothing ... if you have the wrong data on your lable :-) Best regards, Carlos Afonso (South Portugal)'.
    Refs: 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.

  • There is an image of Conus ateralbus on Giancarlo Paganelli's Cone Shell collection page at http://www.molluscs.net/gallery/conidae/ateralbus.html and other images at Hardy's Internet Guide to Marine Gastropods, http://www.gastropods.com/shell_pages/a/Shell_Conus_ateralbus.html.

  • PS. Conus ateralbus also appears on a 50c postage stamp from Cape Verde (date issued 30 November, 1983) . To view the postage stamp, load up this page and scroll down to the third entry, Conus ateralbus - Kiener 1845, then click on Cape Verde Islands.

3 January 2002

    California Cone:
    Check out the description and images of Conus californicus (or California Cone) at the eNature web site. You can even send it as a postcard.

    Shells of the Philippines - Book:
    Fely and Carlos Leobrera owners of Carfel Shell Exports, invite you to go shelling from the comfort of the internet for beautiful and colorful shells of the Philippines. Here they have information about CONIDAE (including Conus gloriamaris, Chemnitz, 1777) and details of the book "Shells of the Philippines" by F.J. Springsteen and F.M. Leobrera, devoted to the identification of mollusks occuring within the Philippines. This book contains over 1,660 images, illustrated in 100 full color plates.

1 January 2002

    New Year Cones !:
    Giancarlo Paganelli has updated his Cone Shells collection (currently currently 555 images), with five new images of Cones - just for the New Year !
    Conus cuneolus Reeve, 1843, Cape Verde, Sal Is. - 27.4 mm; Conus baylei Röckel & da Motta, 1979, Philippines, Mindanao, Aliguay Is. - 24.1 mm; Conus loroisii f. huberorum da Motta, 1990, Sri Lanka - 45.7 mm; Conus pennaceus f. madagascariensis Sowerby II, 1857-58, India - 45.9 mm, and Conus venezuelanus f. tristensis Petuch, 1987, Venezuela - 29.5 mm.

    Conidae images:
    A list of 193 cone shells with associated images is available from Donald Chan's The Molluscs Net web site gallery (Updated November 13, 2001)

    Costa Rican Cones :
    A number of cone shell species are included in a database of molluscs compiled by the Instituto Nacional de Biodiversidad, in Costa Rica. Details of the sites of collection of the following Conus species are available: Conus archon Broderip; Conus brunneus Wood ; Conus chaldeus (Roding); Conus dalli Stearns; Conus diadema Sowerby; Conus ebraeus Linnaeus; Conus fergusoni Sowerby; Conus gladiator Broderip; Conus jaspideus Gmelin; Conus mus Hwass; Conus nux Broderip; Conus patricius Hinds; Conus perplexus Sowerby; Conus princeps Linnaeus; Conus purpurascens Sowerby; Conus regularis Sowerby; Conus virgatus Reeve, and Conus ximenes Gray.

    Cone Shell Postcards:
    Molluscan Pictures and George Sangiouloglou have made it easy for you to send a Cone Shell Postcard. There are 6 cone shell postcards to choose from: Conus milneedwardsi (Andaman sea form) 141 mm; Conus gloriamaris 103.8 mm; Conus hirasei 49.1 mm; Conus kuroharai 62.7 mm; Conus kintoki 68.7 mm, and Conus kinoshitai 61.4 mm. AND they are FREE to send to anyone with an email address. So go to it - send one now !

    French Polynesia - Conus textile Postcard:
    Send this picture as a postcard
    Warning: When snorkeling or scuba diving, NEVER pick up a live cone shell. Certain species such as the Textile Cone (shown) are extemely poisonous and can inflict serious or even fatal stings!
    (Source: Virtual Tourist.Com annk's page)

    Singapore Cones:
    The following list of Conus were extracted from the book: Chou, LM, Ng, PKL and Lim, KKP (1994) (authors of Animalia: Mollusca) "A first look at biodiversity in Singapore". Malacofauna listing : 73 - 78. National Council on the Environment, Ministry of Environment (MOE), Singapore, 163 pages. Source: MOE Shell List.
    Conus achatinus; Conus capitaneus; Conus characteristicus; Conus consors; Conus generalis; Conus glans; Conus gubernator; Conus marmoreus; Conus mustelinus; Conus planorbis; Conus tessulatus; Conus textile, and Conus virgo.

    Venomous Cones:
    Scroll down the following link at Molluscan Pictures to view a list of early books / journal articles on venomous Conus.

    Dangerous Kenyan Cones:
    Conus geographus and Conus textile are both found along the Kenyan coast. While all shells should be handled with care, only two in the Kenyan coastal waters present any real threat. Both are cone shells, and as a general rule it is unwise to pick up living cone shells. Most cone shells are equipped with a needle-like apparatus which shoots out the narrow end of the shell. Conus geographus (at left) and Conus textile (at right) both have potentially dangerous venom. Any stings should be treated similarly to those of venomous fish and medical attention should be obtained as soon as possible.



Continued in What's new in 2001
See also : What's new in 2000, What's new in 1999
What's new in 1998
, What's New in 1997 and What's New in 1996

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