A PIP(2) substitute mediates voltage sensor-pore coupling in KCNQ activation

KCNQ family K(+) channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP(2)) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP(2) 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 PIP(2), can substitute for PIP(2) to mediate VSD-pore coupling. Both PIP(2) 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 PIP(2). We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP(2) regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.