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Molecular Pharmacology

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Research ArticleArticle

Effects of an Agonist, Allosteric Modulator, and Antagonist on Guanosine-γ-[35S]thiotriphosphate Binding to Liposomes with Varying Muscarinic Receptor/Go Protein Stoichiometry

Jan Jakubík, Tatsuya Haga and Stanislav Tuček
Molecular Pharmacology November 1998, 54 (5) 899-906; DOI: https://doi.org/10.1124/mol.54.5.899
Jan Jakubík
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Tatsuya Haga
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Stanislav Tuček
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Abstract

We investigated whether alcuronium, an allosteric modulator of muscarinic acetylcholine receptors, can induce receptor-mediated activation of Go proteins in liposomal membranes incorporating purified M2 receptors and Goproteins and whether its action is affected by the receptor/Go protein (R/Go) ratio. The binding of guanosine-γ-[35S]thiotriphosphate ([35S]GTPγS) served as the indicator of G protein activation. It was stimulated by empty receptors at high receptor densities, and the dose-response curve was shifted to the left by the agonist carbachol and to the right by the antagonist atropine. At an R/Go ratio of 300:100, the rate of [35S]GTPγS binding was the same in the presence or absence of 0.1 mm carbachol. Alcuronium increased the binding of [35S]GTPγS at R/Go ratios of <3:100 and diminished it at R/Go ratios of >10:100, similar to previous observations on intact cells expressing muscarinic receptors at different densities. The apparent biphasicity of alcuronium action indicates that the allosteric modulator has at least two effects on muscarinic receptor/G protein interaction but its mechanistic basis is unclear. The “active state” of muscarinic receptors induced by alcuronium probably is different from that induced by carbachol. Changes in the densities of receptors and Goproteins had little effect on the kinetics of [35S]GTPγS binding and on receptor affinity for carbachol, provided the R/Go ratio was kept constant. This suggests that the receptors and G proteins are located in microdomains in which their concentrations remain constant, despite variations in the amounts of lipidic membranes in the system.

Footnotes

    • Received January 30, 1998.
    • Accepted July 7, 1998.
  • Send reprint requests to: Dr. S. Tuček, Institute of Physiology AV CR, Vı́deňská 1083, 14220 Prague, Czech Republic. E-mail: tucek{at}biomed.cas.cz

  • ↵1 Current affiliation: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892.

  • This work was supported by Grant 309/96/1287 from the Grant Agency of the Czech Republic (S.T.), National Institutes of Health Fogarty International Research Collaboration Award 2-R03-TW00171 (E.E.El-Fakahany), and a Travel Grant of the Japan Society for the Promotion of Science (J.J.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
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Research ArticleArticle

Effects of an Agonist, Allosteric Modulator, and Antagonist on Guanosine-γ-[35S]thiotriphosphate Binding to Liposomes with Varying Muscarinic Receptor/Go Protein Stoichiometry

Jan Jakubík, Tatsuya Haga and Stanislav Tuček
Molecular Pharmacology November 1, 1998, 54 (5) 899-906; DOI: https://doi.org/10.1124/mol.54.5.899

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Research ArticleArticle

Effects of an Agonist, Allosteric Modulator, and Antagonist on Guanosine-γ-[35S]thiotriphosphate Binding to Liposomes with Varying Muscarinic Receptor/Go Protein Stoichiometry

Jan Jakubík, Tatsuya Haga and Stanislav Tuček
Molecular Pharmacology November 1, 1998, 54 (5) 899-906; DOI: https://doi.org/10.1124/mol.54.5.899
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