Abstract：
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 Ca2+ imaging, we show that iloperidone and ifenprodil inhibit the channel activity of recombinant TRPM6 with IC50 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 IC50 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.
摘要：
瞬时受体电位阳离子通道，亚科M,成员6和7（TRPM6和TRPM7）是同源膜蛋白，包含与胞质丝氨酸/苏氨酸蛋白激酶结构域融合的阳离子通道单元。动物疾病模型的临床研究和实验表明，TRPM6和TRPM7电流的选择性抑制可能对免疫和心血管疾病患者有益。肿瘤和其他病理，但是合适的药理学工具包仍然不发达。本研究鉴定了特异性作用于TRPM6和TRPM7的通道部分的小合成分子。使用电生理分析结合Ca2+成像，我们显示伊潘立酮和艾芬普地尔抑制重组TRPM6的通道活性，IC50值为0.73和3.33µM，分别,对TRPM7频道没有影响。我们还发现VER155008抑制TRPM7通道，IC50值为0.11µM，但不影响TRPM6。最后,发现伊潘立酮和VER155008的作用适用于阻断小鼠和人类细胞模型集合中的天然内源性TRPM6和TRPM7.因此，伊潘立酮的鉴定，ifenprodil,和VER155008允许第一次有选择地操纵TRPM6和TRPM7电流。
