Department of Natural Sciences, The Open University of Israel, Ra'anana, Israel.
Department of Natural Sciences, The Open University of Israel, Ra'anana, Israel.
Biochem Pharmacol. 2024 Sep;227:116421. doi: 10.1016/j.bcp.2024.116421. Epub 2024 Jul 10.
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.
毒蕈碱型受体是 G 蛋白偶联受体 (GPCRs)，在各种生理功能中发挥作用。先前的研究表明，这些受体与其他 GPCR 一样，对电压敏感；它们对激动剂的亲和力和激活都受膜电位调节。据我们所知，拮抗剂对这些受体的作用是否与电压有关尚未得到研究。在这项研究中，我们使用表达 M2 毒蕈碱受体 (M2R) 的非洲爪蟾卵母细胞来研究这个问题。我们的结果表明，两种 M2R 拮抗剂阿托品和东莨菪碱的效力与电压有关；它们在静息电位下比去极化时更有效。相比之下，M2R 拮抗剂 AF-DX 386 则没有表现出电压依赖性效力。此外，我们发现，在两种变构调节剂——负调节剂箭毒和正调节剂 LY2119620 的存在下，乙酰胆碱激活 M2R 的电压依赖性保持不变。这些发现增强了我们对 GPCR 电压依赖性的理解，可能具有药理学意义。
