Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany.
Rudolf-Boehm Institute of Pharmacology and Toxicology, Leipzig University, Leipzig, Germany.
Cell Calcium. 2022 Sep;106:102640. doi: 10.1016/j.ceca.2022.102640. Epub 2022 Aug 17.
The transient receptor potential cation channel, subfamily M, members 6 and 7 (TRPM6 and TRPM7) are homologous membrane proteins encompassing cation channel units fused to cytosolic serine/threonine-protein kinase domains. Clinical studies and experiments with animal disease models suggested that selective inhibition of TRPM6 and TRPM7 currents might be beneficial for subjects with immune and cardiovascular disorders, tumours and other pathologies, but the suitable pharmacological toolkit remains underdeveloped. The present study identified small synthetic molecules acting specifically on the channel moieties of TRPM6 and TRPM7. Using electrophysiological analysis in conjunction with Ca imaging, we show that iloperidone and ifenprodil inhibit the channel activity of recombinant TRPM6 with IC values of 0.73 and 3.33 µM, respectively, without an impact on the TRPM7 channel. We also found that VER155008 suppresses the TRPM7 channel with an IC value of 0.11 µM but does not affect TRPM6. Finally, the effects of iloperidone and VER155008 were found to be suitable for blocking native endogenous TRPM6 and TRPM7 in a collection of mouse and human cell models. Hence, the identification of iloperidone, ifenprodil, and VER155008 allows for the first time to selectively manipulate TRPM6 and TRPM7 currents.
瞬时受体电位阳离子通道亚家族 M，成员 6 和 7（TRPM6 和 TRPM7）是同源膜蛋白，包含融合胞质丝氨酸/苏氨酸蛋白激酶结构域的阳离子通道单元。临床研究和动物疾病模型实验表明，选择性抑制 TRPM6 和 TRPM7 电流可能对免疫和心血管疾病、肿瘤和其他病理患者有益，但合适的药理学工具包仍未得到充分发展。本研究鉴定了专门作用于 TRPM6 和 TRPM7 通道部分的小分子合成物。通过电生理学分析结合 Ca 成像，我们表明异丙啶和ifenprodil 分别以 0.73 和 3.33 μM 的 IC 值抑制重组 TRPM6 的通道活性，而对 TRPM7 通道没有影响。我们还发现 VER155008 以 0.11 μM 的 IC 值抑制 TRPM7 通道，但不影响 TRPM6。最后，发现异丙啶和 VER155008 的作用适合在一系列小鼠和人类细胞模型中阻断内源性的 TRPM6 和 TRPM7。因此，异丙啶、ifenprodil 和 VER155008 的鉴定首次允许选择性地操纵 TRPM6 和 TRPM7 电流。
