A PIP2 substitute mediates voltage sensor-pore coupling in KCNQ activation

Yongfeng Liu, Xianjin Xu, Junyuan Gao, Moawiah M. Naffaa, Hongwu Liang, Jingyi Shi, Hong Zhan Wang, Nien Du Yang, Panpan Hou, Wenshan Zhao, Kelli Mc Farland White, Wenjuan Kong, Alex Dou, Amy Cui, Guohui Zhang, Ira S. Cohen, Xiaoqin Zou, Jianmin Cui

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


KCNQ family K+ channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP2) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP2 was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP2, can substitute for PIP2 to mediate VSD-pore coupling. Both PIP2 and CP1 interact with residues amongst a cluster of amino acids critical for VSD-pore coupling. CP1 alters KCNQ channel function due to different interactions with KCNQ compared with PIP2. We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP2 regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.

Original languageEnglish
Article number385
JournalCommunications Biology
Issue number1
StatePublished - Dec 1 2020


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