The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Karem, Jerusalem, 9112102, Israel.
Commun Biol. 2024 Mar 27;7(1):369. doi: 10.1038/s42003-024-06054-3.
Transient receptor potential melastatin 5 (TRPM5) is a calcium-activated monovalent-specific ion channel involved in insulin secretion and taste transduction, making it an attractive target for drug development in various pathologies. While TRPM5 activation involves ligand binding to Gq/G-protein coupled receptors (GPCR) and subsequent elevation of intracellular calcium levels, recent reports suggest the need for additional molecular determinants. Hence, the mechanism of TRPM5 activation remains to be elucidated. Here, we show that PKC phosphorylation and the elevation of intracellular Ca levels are required for TRPM5 activation, with PKC phosphorylation being crucial for channel-evoked currents, primarily at physiological membrane potentials. In contrast, physiological relevant calcium levels alone only induce TRPM5 activation at positive voltages. Our findings highlight the necessity of coordinated intracellular calcium release and PKC phosphorylation for TRPM5 activation. Thus, our results suggest that regulation of PKC activity could be a promising therapeutic target for diseases associated with TRPM5 modulation.
瞬时受体电位阳离子通道亚家族 M 成员 5（TRPM5）是一种钙激活的单价特异性离子通道，参与胰岛素分泌和味觉转导，使其成为各种病理情况下药物开发的有吸引力的靶点。虽然 TRPM5 的激活涉及配体与 Gq/G 蛋白偶联受体（GPCR）的结合，以及随后细胞内钙水平的升高，但最近的报告表明需要额外的分子决定因素。因此，TRPM5 的激活机制仍有待阐明。在这里，我们表明 PKC 磷酸化和细胞内钙水平的升高是 TRPM5 激活所必需的，PKC 磷酸化对于通道诱发的电流至关重要，主要在生理膜电位下。相比之下，仅在正电压下，生理相关的钙水平才会单独诱导 TRPM5 的激活。我们的研究结果强调了细胞内钙释放和 PKC 磷酸化的协调对于 TRPM5 激活的必要性。因此，我们的结果表明，调节 PKC 活性可能是与 TRPM5 调节相关的疾病的有前途的治疗靶点。
