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Activation of muscarinic acetylcholine receptors via their allosteric binding sites

Proceedings of the National Academy of Sciences of the United States of America. 1996 Aug 06 ; 93 (16) : 8705-9.

Proc Natl Acad Sci U S A
ISSN 0027-8424
Source

Language English Country United States Media print

Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.

Persistent link https://www.medvik.cz/link/pmid08710935

Online Full text

PubMed 8710935
PubMed Central PMC38737
DOI 10.1073/pnas.93.16.8705
Knihovny.cz E-resources

MeSH
Muscarinic Agonists pharmacology MeSH
Alcuronium pharmacology MeSH
Allosteric Regulation MeSH
Cyclic AMP metabolism MeSH
Muscarinic Antagonists pharmacology MeSH
Quinuclidinyl Benzilate pharmacology MeSH
CHO Cells MeSH
Inositol Phosphates physiology MeSH
Cricetinae MeSH
Periodicity MeSH
GTP-Binding Proteins physiology MeSH
Receptors, Muscarinic physiology MeSH
Recombinant Proteins MeSH
Signal Transduction MeSH
Strychnine pharmacology MeSH
Transfection MeSH
Gallamine Triethiodide pharmacology MeSH
Animals MeSH
Check Tag
Cricetinae MeSH
Animals MeSH
Publication type
Journal Article MeSH
Research Support, Non-U.S. Gov't MeSH
Research Support, U.S. Gov't, P.H.S. MeSH
Names of Substances
Muscarinic Agonists MeSH
Alcuronium MeSH
Cyclic AMP MeSH
Muscarinic Antagonists MeSH
Quinuclidinyl Benzilate MeSH
Inositol Phosphates MeSH
GTP-Binding Proteins MeSH
Receptors, Muscarinic MeSH
Recombinant Proteins MeSH
Strychnine MeSH
Gallamine Triethiodide MeSH

Ligands that bind to the allosteric-binding sites on muscarinic acetylcholine receptors alter the conformation of the classical-binding sites of these receptors and either diminish or increase their affinity for muscarinic agonists and classical antagonists. It is not known whether the resulting conformational change also affects the interaction between the receptors and the G proteins. We have now found that the muscarinic receptor allosteric modulators alcuronium, gallamine, and strychnine (acting in the absence of an agonist) alter the synthesis of cAMP in Chinese hamster ovary (CHO) cells expressing the M2 or the M4 subtype of muscarinic receptors in the same direction as the agonist carbachol. In addition, most of their effects on the production of inositol phosphates in CHO cells expressing the M1 or the M3 muscarinic receptor subtypes are also similar to (although much weaker than) those of carbachol. The agonist-like effects of the allosteric modulators are not observed in CHO cells that have not been transfected with the gene for any of the subtypes of muscarinic receptors. The effects of alcuronium on the formation of cAMP and inositol phosphates are not prevented by the classical muscarinic antagonist quinuclidinyl benzilate. These observations demonstrate for the first time that the G protein-mediated functional responses of muscarinic receptors can be evoked not only from their classical, but also from their allosteric, binding sites. This represents a new mechanism of receptor activation.

Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

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