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Alpha- alphaA- & psi-Conotoxins and the Nicotinic Acetylcholine Receptor 

The nicotinic acetylcholine receptor is a ligand-gated ion channel . The ion channel is formed from the assembly of a membrane protein oligomer (a pentamer) that binds the neurotransmitter, acetylcholine. It also binds agonists such as nicotine and nicotinic antagonists such as mecamylamine.

The binding of acetylcholine or nicotine to the alpha subunit of the receptor induces a conformational change which allows the influx of sodium and calcium into the cell. This influx causes membrane depolarisation and the activation of voltage-gated ion channels for sodium and calcium, resulting in the exocytotic release of neurotransmitters and hormones from vesicular stores.

Muscle-type and neuronal-type nicotinic receptors are known . 
Nicotinic acetylcholine receptors are found in muscle and neuronal tissues. The muscle-type nicotinic receptor is composed of four different subunits (alpha, beta, gamma and delta) each of molecular weight 40-60 kDa. These are arranged in the membrane as a pentameric complex comprising two alpha*, one beta, one gamma and a delta subunit. When glycosylated as in the native state, the pentamer has a molecular weight of ~ 290 kDa and two of these pentamers associate by disulphide bonding to form the receptor. The muscle-type nicotinic receptor is inhibited by alpha conotoxins from piscivorous Conidae such as C. geographus , C. magus and C. ermineus. 

*[It is now possible to selectively block either of the two acetylcholine binding sites on the alpha subunits of Torpedo nicotinic receptors using either alpha-Ctx MI or EI, (Martinez et al 1995)]

In addition,  nicotinic receptors at the neuromuscular junction  are inhibited competitively by alphaA-conotoxin (eg. alphaA PIVA, see Hopkins et al 1995; Jacobsen et al 1997, JBC 272: 22531-7) and non-competitively by psi-conotoxin from C.purpurascens (eg. psi-PIIIE, the first non-competitive nAChR-blocking conotoxin; Shon et al 1997a).

The neuronal-type nicotinic receptor is also a pentamer but has no gamma or delta subunits. It is comprised of only alpha and beta subunits. The neuronal-type nicotinic receptor is inhibited by alpha conotoxins from molluscivorus Conidae such as C. imperialis and C. pennaceus.

Alpha Conotoxins inhibit the nicotinic receptor-ionophore complex

Alpha conotoxins were the first toxins isolated from conus venom and were designated alpha because they have the same action as the alpha neurotoxins from snake venoms (eg. alpha bungarotoxin) which inhibit the nicotinic receptor.

The alpha-conotoxins GI, GIA, and GII (from Conus geographus ) and MI (from Conus magus) are homologous peptides of 13 and 15 amino acids respectively. Each contains two disulphide bridges and has a highly basic region of primary sequence.

The sequences and biological activities of 10 naturally occurring apha-conotoxins have been published. Click here to view the sequences.

These alpha conotoxins cause postsynaptic inhibition at the neuromuscular junction resulting in paralysis and death. The symptoms resemble those of curare poisoning with eventual respiratory failure.

An account of death by cone shell envenomation that occurred at Haymen Island on the Great Barrier Reef, Australia in 1935 is given in the April 4, 1936 issue of The Medical Journal of Australia.

The mechanism by which paralysis is brought about is thought to involve the alpha conotoxins binding to the alpha subunit of the nicotinic ligand-gated ion channel and blocking the binding of acetylcholine and of agonists such as nicotine. By preventing the agonist-induced conformational change in the receptor ion channel required for the influx of sodium that is essential for membrane depolarisation, the alpha conotoxins inhibit neurotransmitter action and induce paralysis. 
 


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CG and BGL, December-97


 
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