Snake toxins with high selectivity for subtypes of muscarinic acetylcholine receptors

There are five subtypes of muscarinic acetylcholine receptors (M-1 to M-5) which control a large number of physiological processes, such as the functi on of heart and smooth muscles, glandular secretion, release of neurotransm itters, gene expression and cognitive functions as learning and memory. A s elective ligand is very useful for studying the function of a subtype in pr esence of other subtypes, which is the most common situation, since a cell or an organ usually has several subtypes. There are many non-selective musc arinic ligands, but only few selective ones. Mambas, African snakes of genu s Dendroaspis have toxins, muscarinic toxins, that are selective for M-1, M -2 and M-4 receptors. They consist of 63-66 amino acids and four disulfides which form four loops. They are members of a large group of snake toxins, three-finger toxins; three loops are extended like the middle fingers of a hand and the disulfides and the shortest loop are in the palm of the hand. Some of the toxins target the allosteric site which is located in a cleft o f the receptor molecule close to its extracellular part. A possible explana tion to the good selectivity is that the toxins bind to the allosteric site , but because of their size they probably also bind to extracellular parts of the receptors which are rather different in the various subtypes. Some o ther allosteric ligands also have good selectivity, the alkaloid brucine an d derivatives are selective for M-1, M-3 and M-4 receptors. Muscarinic toxi ns have been used in several types of experiments. For instance radioactive ly labeled M-1 and M-4 selective toxins were used in autoradiography of hip pocampus from Alzheimer patients. One significant change in the receptor co ntent was detected in one region of the hippocampus, dentate gyrus, where M -4 receptors were reduced by 50% in patients as compared to age-matched con trols. Hippocampus is essential for memory consolidation. M-4 receptors in dentate gyrus may play a role, since they decreased in Alzheimers disease w hich destroys the memory. Another indication of the role of M-4 receptors f or memory is that injection of the M-4 selective antagonist muscarinic toxi n 3 (M-4-toxin 1) into rat hippocampus produced amnesia. (C) 2000 Societe f rancaise de biochimie et biologie moleculaire / Editions scientifiques et m edicales Elsevier SAS.