Snake toxins with high selectivity for subtypes of muscarinic acetylcholine receptors

Evert Karlsson, Mikael Jolkkonen, Ezra Mulugeta, Pierluigi Onali, Abdu Adem

Research output: Contribution to journalReview articlepeer-review

93 Citations (Scopus)

Abstract

There are five subtypes of muscarinic acetylcholine receptors (M1 to M5) which control a large number of physiological processes, such as the function of heart and smooth muscles, glandular secretion, release of neurotransmitters, gene expression and cognitive functions as learning and memory. A selective ligand is very useful for studying the function of a subtype in presence of other subtypes, which is the most common situation, since a cell or an organ usually has several subtypes. There are many non-selective muscarinic ligands, but only few selective ones. Mambas, African snakes of genus Dendroaspis have toxins, muscarinic toxins, that are selective for M1, M2 and M4 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 of the receptor molecule close to its extracellular part. A possible explanation 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 other allosteric ligands also have good selectivity, the alkaloid brucine and derivatives are selective for M1, M3 and M4 receptors. Muscarinic toxins have been used in several types of experiments. For instance radioactively labeled M1 and M4 selective toxins were used in autoradiography of hippocampus from Alzheimer patients. One significant change in the receptor content was detected in one region of the hippocampus, dentate gyrus, where M4 receptors were reduced by 50% in patients as compared to age-matched controls. Hippocampus is essential for memory consolidation. M4 receptors in dentate gyrus may play a role, since they decreased in Alzheimers disease which destroys the memory. Another indication of the role of M4 receptors for memory is that injection of the M4 selective antagonist muscarinic toxin 3 (M4-toxin 1) into rat hippocampus produced amnesia. (C) 2000 Societe francaise de biochimie et biologie moleculaire / Editions scientifiques et medicales Elsevier SAS.

Original languageEnglish
Pages (from-to)793-806
Number of pages14
JournalBiochimie
Volume82
Issue number9-10
DOIs
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Biochemistry

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