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Research ArticleCELLULAR AND MOLECULAR

Allosteric Modulation by Persistent Binding of Xanomeline of the Interaction of Competitive Ligands with the M1 Muscarinic Acetylcholine Receptor

Jan Jakubı́k, Stanislav Tuček and Esam E. El-Fakahany
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 1033-1041; DOI: https://doi.org/10.1124/jpet.301.3.1033
Jan Jakubı́k
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Stanislav Tuček
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Esam E. El-Fakahany
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Abstract

Xanomeline is a potent agonist that is functionally selective for muscarinic M1 receptors. We have shown previously that a significant fraction of xanomeline binding to membranes of Chinese hamster ovary (CHO) cells expressing the M1 receptors occurs in a wash-resistant manner and speculated that this persistent binding likely does not take place at the primary binding site on the receptor. In the present work we investigated in depth the pharmacological characteristics of this unique mode of xanomeline binding and the effects of this binding on the interaction of classical competitive ligands with the receptor in CHO cells that express the M1 muscarinic receptor. Onset of persistent binding of xanomeline to the M1 muscarinic receptor was fast and was only slightly hindered by atropine. Its dissociation was extremely slow, with a half-life of over 30 h. Although persistently bound xanomeline strongly inhibited binding of the classical antagonistN-methylscopolamine (NMS) to the receptor, there are multiple indications that this is not the result of competition at the same binding domain. Namely, wash-resistant binding of xanomeline only slightly slowed the rate of NMS association, but enhanced the rate of NMS dissociation. Moreover, preincubation with xanomeline followed by extensive washing brought about an apparent decrease in the number of NMS binding sites. Our findings are best interpreted in terms of allosteric interactions between xanomeline-persistent binding to the M1 muscarinic receptor and competitive ligands bound to the classical receptor binding site.

Footnotes

  • This work was supported by National Institutes of Health Grant NS25743 (to E.E.E.-F.) and Grant Agency of the Czech Republic Grant GP305/01/D119 (to J.J.).

  • Abbreviations:
    NMS
    N-methylscopolamine
    CHO
    Chinese hamster ovary
    • Received December 11, 2001.
    • Accepted February 18, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleCELLULAR AND MOLECULAR

Allosteric Modulation by Persistent Binding of Xanomeline of the Interaction of Competitive Ligands with the M1 Muscarinic Acetylcholine Receptor

Jan Jakubı́k, Stanislav Tuček and Esam E. El-Fakahany
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1033-1041; DOI: https://doi.org/10.1124/jpet.301.3.1033

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Research ArticleCELLULAR AND MOLECULAR

Allosteric Modulation by Persistent Binding of Xanomeline of the Interaction of Competitive Ligands with the M1 Muscarinic Acetylcholine Receptor

Jan Jakubı́k, Stanislav Tuček and Esam E. El-Fakahany
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1033-1041; DOI: https://doi.org/10.1124/jpet.301.3.1033
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