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.
摘要：
毒蕈碱受体是在各种生理功能中起作用的G蛋白偶联受体(GPCRs)。以前的研究表明，这些受体，以及其他GPCRs，是电压敏感的；它们对激动剂的亲和力及其激活均受膜电位调节。据我们所知,拮抗剂对这些受体的作用是否具有电压依赖性尚未研究.在这项研究中,我们使用表达M2毒蕈碱受体（M2R）的非洲爪的卵母细胞来研究这个问题。我们的结果表明，两种M2R拮抗剂的效力，阿托品和东莨菪碱,是电压依赖性的；它们在静息电位下比在去极化下更有效。相比之下,M2R拮抗剂AF-DX386未表现出电压依赖性效力.此外，我们发现，在存在两种变构调节剂的情况下，乙酰胆碱对M2R激活的电压依赖性保持不变，负调节剂没食子胺和正调节剂LY2119620。这些发现增强了我们对GPCRs电压依赖性的理解，并可能具有药理意义。
