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Mechanism of alpha conotoxin action:

Alpha conotoxins compete with the acetylcholine receptor antagonists d-tubocurarine and alpha-bungarotoxin for the nicotinic acetylcholine receptor binding site. The binding is reversible (Gray et al, 1981 ) and paralysis is induced more quickly compared to that of alpha-bungarotoxin.

The muscle-type nicotinic acetylcholine receptor contains two binding sites for acetylcholine that can be distinguished pharmacologically. The affinities of several alpha-conotoxins for these two binding sites on nicotinic receptors from BC3H1 cells and Torpedo electric organ have been studied by Groebe et al (1995), Hann et al (1994) and Martinez et al 1995.

It is now possible to selectively block either of the two ligand binding sites of Torpedo receptors using either alpha-Ctx MI or EI. The functional effects of alpha-conotoxin EI vs MI also differ in mammalian AChRs (Martinez et al 1995 ).

alpha-Conotoxins MI (from C. magus), GI (from C. geographus), and SIA (from C. striatus) each inhibited the binding of 125I-alpha-bungarotoxin to nicotinic acetylcholine receptors on BC3H1 cells with two distinct and independent affinities, which differed by >10,000-fold. The affinities of alpha-conotoxins SI and SII were significantly lower (EC50s micromolar vs. nanomolar) and the differences in the affinities of each of these toxins for the two sites were <400-fold.

The micromolar EC50 values of SI and SII are consistent with the observation that these peptides are substantially less toxic than alpha-conotoxins MI and GI after intraperitoneal injection into mice (Zafaralla et al 1988 ).

alpha-Conotoxins MI, GI, and SIA and SI had a 15,000-fold higher affinity for the acetylcholine binding site near the alpha/delta subunit interface of nicotinic receptors from BC3H1 cells. However, when assessed using nicotinic receptors from Torpedo electric organ, alpha-conotoxin MI displayed higher affinity for the acetylcholine binding site near the alpha/gamma subunit interface (Groebe, et al 1995 ).

These observations suggest that species variations in the sequences of the gamma and delta subunits resulted in a dramatic reversal of the relative affinities of the alpha-conotoxins for each acetylcholine binding site.

The remarkable differences in the affinities of alpha-conotoxin MI for the alpha/delta (decrease of 1500-fold) and alpha/gamma sites (increase of 8500-fold) between BC3H1 cell and Torpedo nicotinic receptors, respectively, suggest that caution should be exercised when alpha-conotoxins are used to pharmacologically define nicotinic receptor subtypes in different species.

These observations of site-selective nicotinic receptor antagonists also have a number of practical implications .

References:

Gray, W.R., Luque, A., Olivera, B.M., Barrett, J. and Cruz, L.J. (1981) Peptide toxins from Conus geographus venom. J. Biol. Chem. 256: 4734-4740.

Groebe, D.R., Dumm, J.M., Levitan, E.S. and Abramson, S.N. (1995) alpha-Conotoxins selectively inhibit one of the two acetylcholine binding sites of nicotinic receptors. Molecular Pharmacology 48: 105-111.

Hann, R. M., Pagan, O. R. and Eterovic, V.A. (1994) The alpha-conotoxins GI and MI distinguish between the nicotinic receptor agonist sites while SI does not. Biochemistry 33:14058-14063.

Zafaralla, G.C., Ramilo, C., Gray, W.R., Karlstrom, R., Olivera, B.M. and Cruz, L.J. (1988) Phylogenetic specificity of cholinergic ligands: alpha-conotoxin SI. Biochemistry 27: 7102-7105.

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

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BGL, October-95


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