TY - JOUR
T1 - A PIP2 substitute mediates voltage sensor-pore coupling in KCNQ activation
AU - Liu, Yongfeng
AU - Xu, Xianjin
AU - Gao, Junyuan
AU - Naffaa, Moawiah M.
AU - Liang, Hongwu
AU - Shi, Jingyi
AU - Wang, Hong Zhan
AU - Yang, Nien Du
AU - Hou, Panpan
AU - Zhao, Wenshan
AU - White, Kelli Mc Farland
AU - Kong, Wenjuan
AU - Dou, Alex
AU - Cui, Amy
AU - Zhang, Guohui
AU - Cohen, Ira S.
AU - Zou, Xiaoqin
AU - Cui, Jianmin
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088153276&partnerID=8YFLogxK
U2 - 10.1038/s42003-020-1104-0
DO - 10.1038/s42003-020-1104-0
M3 - Article
C2 - 32678288
AN - SCOPUS:85088153276
SN - 2399-3642
VL - 3
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 385
ER -