A—Conotoxin Mil

Fig. 3 Potential subunit compositions of nAChRs expressed in dopaminergic nerve terminals. A combination of ligand binding ([ H]-epibatidine and [ I]-a-conotoxin Mil), immunoprecipita-tion, and dopamine release data have led to the conclusion that rodent brain expresses a minimum of five different nAChR subtypes. Three of these (the two forms of a4p2 and a4aSP2) do not bind a-conotoxin Mil with high affinity (a-conotoxin Mll-resistant). The three a6-containing subtypes bind a-conotoxin Mil with high affinity (conotoxin Mil-sensitive). In general, the conotoxin-sensitive nAChR subtypes are activated by lower concentrations of agonist than are required to activate the a-conotoxin Mll-resistant subtypes (Salminen et al. 2007)...

Salminen O, Drapeau J, McIntosh JM, CoUins AC, Marks MJ, Grady SR (2007) Pharmacology of a-conotoxin Mil-sensitive subtypes of nicotinic acetylcholine receptors isolated by breeding of null mutant mice. Mol Pharmacol 71 1563-1571... 

The a-conotoxins of cone snails, twelve to sixteen amino acids in length, are among the smallest known peptidic, nAChR antagonists (Fig. 8.40). [132,133] These bind with remarkable selectivity at the different subtypes of neuronal nicotinic receptors and at those of the neuromuscular endplate. The a-conotoxin Mil (GlyCysCysSerAsnProValCysHisLeuGluHisSerAsnLeuCysNH2 [134]) from Conus magnus, for instance, inhibits the (a3)2(P2)3"teceptor in the low to sub-nanomolar region, with a > 200-fold selectivity over related receptors. 

Salminen, O., Whiteaker, P., Grady, S.R., Collins, A.C., McIntosh, J.M., Marks, M.J. The subunit composition and pharmacology of alpha-Conotoxin Mil-binding nicotinic acetylcholine receptors studied by a novel membrane-binding assay. Neuropharmacology. 48 696, 2005. 

Kulak JM, Nguyen TA, Olivera BM, McIntosh JM (1997) Alpha-conotoxin Mil blocks nicotine-stimulated dopamine release in rat striatal synaptosomes. J Neurosci 17 5263-5270 Kuryatov A, Gerzanich V, Nelson M, Olale F, Lindstrom J (1997) Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca + permeabihty, conductance, and gating of human a4 32 nicotinic acetylcholine receptors, J Neurosci 17 9035-9047 Kuryatov A, Olale FA, Choi C, Lindstrom J (2000) Acetylchohne receptor extracellular domain determines sensitivity to nicotine-induced inactivation, Eur J Pharmacol 393 11-21 Langley JN (1880) On the antagonism of poisons. J Physiol 3 11-21... 

Clark RJ, Fischer H, Dempster L, Daly NL, Rosengren KJ, Nevin ST, Meunier FA, Adams DJ, Craik DJ (2005) Engineering stable peptide toxins by means of backbone cyclization stabilization of the alpha-conotoxin MIL Proc Natl Acad Sci U S A 102 13767-13772... 

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