Voltage dependence of M2 muscarinic receptor antagonists and allosteric modulators

Shimrit Hazan, Merav Tauber, Yair Ben-Chaim

Research output: Contribution to journalArticlepeer-review

Abstract

Muscarinic receptors are G protein-coupled receptors (GPCRs) that play a role in various physiological functions. Previous studies have shown that these receptors, along with other GPCRs, are voltage-sensitive; both their affinity toward agonists and their activation are regulated by membrane potential. To our knowledge, whether the effect of antagonists on these receptors is voltage-dependent has not yet been studied. In this study, we used Xenopus oocytes expressing the M2 muscarinic receptor (M2R) to investigate this question. Our results indicate that the potencies of two M2R antagonists, atropine and scopolamine, are voltage-dependent; they are more effective at resting potential than under depolarization. In contrast, the M2R antagonist AF-DX 386 did not exhibit voltage-dependent potency.Furthermore, we discovered that the voltage dependence of M2R activation by acetylcholine remains unchanged in the presence of two allosteric modulators, the negative modulator gallamine and the positive modulator LY2119620. These findings enhance our understanding of GPCRs’ voltage dependence and may have pharmacological implications.

Original languageEnglish
Article number116421
Pages (from-to)116421
JournalBiochemical Pharmacology
Volume227
DOIs
StatePublished - Sep 2024

Keywords

  • Allosteric modulators
  • Antagonists
  • G protein coupled receptors
  • Muscarinic receptors
  • Voltage dependence
  • Xenopus oocytes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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