Huang Yuan, Ma Demin, Yang Zhenni, Zhao Yiwen, Guo Jiangtao
Department of Cardiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Biochem Biophys Res Commun. 2023 Dec 31;689:149218. doi: 10.1016/j.bbrc.2023.149218. Epub 2023 Nov 9.
KCNQ (Kv7) channels are voltage-gated, phosphatidylinositol 4,5-bisphosphate- (PIP-) modulated potassium channels that play essential roles in regulating the activity of neurons and cardiac myocytes. Hundreds of mutations in KCNQ channels are closely related to various cardiac and neurological disorders, such as long QT syndrome, epilepsy, and deafness, which makes KCNQ channels important drug targets. During the past several years, the application of single-particle cryo-electron microscopy (cryo-EM) technique in the structure determination of KCNQ channels has greatly advanced our understanding of their molecular mechanisms. In this review, we summarize the currently available structures of KCNQ channels, analyze their special voltage gating mechanism, and discuss their activation mechanisms by both the endogenous membrane lipid and the exogenous synthetic ligands. These structural studies of KCNQ channels will guide the development of drugs targeting KCNQ channels.
KCNQ（Kv7）通道是电压门控的、磷脂酰肌醇4,5-二磷酸（PIP）调节的钾通道，在调节神经元和心肌细胞的活性中起重要作用。KCNQ通道中的数百种突变与各种心脏和神经疾病密切相关，如长QT综合征、癫痫和耳聋，这使得KCNQ通道成为重要的药物靶点。在过去几年中，单颗粒冷冻电子显微镜（cryo-EM）技术在KCNQ通道结构测定中的应用极大地推进了我们对其分子机制的理解。在这篇综述中，我们总结了KCNQ通道目前可用的结构，分析了它们特殊的电压门控机制，并讨论了内源性膜脂和外源性合成配体对它们的激活机制。这些对KCNQ通道的结构研究将指导靶向KCNQ通道的药物开发。
