Muscarinic receptor subtype selective toxins

The muscarinic acetylcholine receptors are monomeric proteins with seven hydrophobic, membrane spanning helices, and share a common evolutionary origin with the other members of the superfamily of membrane proteins known as seven-helix receptors. The amino acid sequences of five different muscarinic acetylcholine receptors, called m1, m2, m3, m4 and m5 have been determined. The five subtypes are expressed to different extent in different tissues. A large number of low molecular ligands for muscarinic receptors are known, but they bind to all five subtypes of receptors and only a few of them have a slightly higher (five-six fold) affinity for one of the subtypes, e.g. pirenzepine for M1 (1) and tripitramine for M2 receptors (2). Several neurotoxins have been isolated from snake venoms and used as pharmacological tools. Mambas, African snakes of genus Dendroaspis, have toxins that recognize muscrinic receptors and some of these muscarinic toxins are the most selective ligands for M1 and M4 receptors known to date.