Key result
The compound CP1 substitutes for PIP2 to mediate voltage sensor-pore coupling in KCNQ1 channels and reverses drug-induced action potential prolongation in ventricular myocytes.
Why the study?
KCNQ family K+ channels require PIP2 for voltage-dependent activation, but the structural basis and potential for a substitute to mediate voltage sensor domain-pore coupling remained to be explored.
The identification of CP1 as a PIP2 substitute that mediates VSD-pore coupling in KCNQ channels provides a structural basis for channel regulation and a potential target for anti-arrhythmic therapy.
CP1 provides a structural probe for KCNQ gating; leaves open any therapeutic role in channelopathies pending validation.
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.
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Liu et al. (2020) studied KCNQ channel activation. CP1 vs. Control (absence of CP1 or PIP2 depletion) was evaluated on KCNQ1 channel activation and VSD-pore coupling. The compound CP1 substitutes for PIP2 to mediate voltage sensor-pore coupling in KCNQ1 channels and reverses drug-induced action potential prolongation in ventricular myocytes.
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