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

Author:

Liu YongfengORCID,Xu Xianjin,Gao Junyuan,Naffaa Moawiah M.,Liang Hongwu,Shi Jingyi,Wang Hong ZhanORCID,Yang Nien-DuORCID,Hou PanpanORCID,Zhao Wenshan,White Kelli McFarland,Kong Wenjuan,Dou Alex,Cui Amy,Zhang Guohui,Cohen Ira S.,Zou Xiaoqin,Cui JianminORCID

Abstract

AbstractKCNQ 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.

Funder

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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