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Research ArticleCELLULAR AND MOLECULAR

Allosteric Modulation of Muscarinic Receptor Signaling: Alcuronium-Induced Conversion of Pilocarpine from an Agonist into an Antagonist

Katrin Zahn, Niels Eckstein, Christian Tränkle, Wolfgang Sadée and Klaus Mohr
Journal of Pharmacology and Experimental Therapeutics May 2002, 301 (2) 720-728; DOI: https://doi.org/10.1124/jpet.301.2.720
Katrin Zahn
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Niels Eckstein
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Christian Tränkle
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Wolfgang Sadée
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Klaus Mohr
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Abstract

Previous studies on allosteric interactions at muscarinic receptors have often focused on ligand-receptor binding interactions, because ligand binding seemed to reflect functional consequences. The prototypal allosteric agent alcuronium is known to bind with similar affinity to the M2 subtype of muscarinic acetylcholine receptors whether or not the receptors are occupied by the agonist pilocarpine. To determine allosteric modulation of receptor signaling by alcuronium, the effects of pilocarpine were measured in contracting guinea pig left atria and on G-protein coupling in M2-transfected Chinese hamster ovary (CHO) cell membranes. Alcuronium dose-dependently suppressed pilocarpine-induced reduction of isometric contraction force in atria (pIC50, Alc = 5.63) without any effect on the EC50 of pilocarpine, consistent with an allosteric mechanism. In contrast, alcuronium shifted the concentration-effect curve of the agonist oxotremorine M to the right without affecting the maximal effect, in a formally competitive manner (pKA, Alc = 5.54). If pilocarpine remained receptor bound in the presence of alcuronium, this indicates that pilocarpine can no longer act as an agonist. In support of this hypothesis, pilocarpine acted as a competitive antagonist against oxotremorine M in the presence of 10 μM alcuronium. Measuring guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding in CHO-M2 membranes yielded similar results. Alcuronium suppressed pilocarpine-induced stimulation of [35S]GTPγS binding (pIC50, Alc = 5.47) without shift in EC50, whereas it competitively shifted the response to oxotremorine M (pKA, Alc = 5.97). [3H]Oxotremorine M binding data corresponded with the functional findings. In conclusion, alcuronium converted the agonist pilocarpine into an antagonist—a novel type of functional allosteric interaction.

Footnotes

  • The work was supported by grants provided by the Deutsche Forschungsgemeinschaft (to K.M.) and by the German Academic Exchange Service, DAAD (to N.E.).

  • Abbreviations:
    ANOVA
    analysis of variance
    M2 receptor
    M2 subtype of muscarinic acetylcholine receptor
    CF
    contraction force
    CHO cells
    Chinese hamster ovary cells
    GTPγS
    guanosine-γ-thiotriphosphate
    NMS
    N-methylscopolamine
    • Received November 26, 2001.
    • Accepted January 25, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 2
1 May 2002
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Research ArticleCELLULAR AND MOLECULAR

Allosteric Modulation of Muscarinic Receptor Signaling: Alcuronium-Induced Conversion of Pilocarpine from an Agonist into an Antagonist

Katrin Zahn, Niels Eckstein, Christian Tränkle, Wolfgang Sadée and Klaus Mohr
Journal of Pharmacology and Experimental Therapeutics May 1, 2002, 301 (2) 720-728; DOI: https://doi.org/10.1124/jpet.301.2.720

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Research ArticleCELLULAR AND MOLECULAR

Allosteric Modulation of Muscarinic Receptor Signaling: Alcuronium-Induced Conversion of Pilocarpine from an Agonist into an Antagonist

Katrin Zahn, Niels Eckstein, Christian Tränkle, Wolfgang Sadée and Klaus Mohr
Journal of Pharmacology and Experimental Therapeutics May 1, 2002, 301 (2) 720-728; DOI: https://doi.org/10.1124/jpet.301.2.720
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