Two PIP2 molecules perform distinct roles in IKs channel activation: V-PIP2 enables the bent-to-straight transition, whereas C-PIP2 mediates VSD-pore coupling, a mechanism selectively targeted by compound CA1.
The study elucidates the distinct roles of two PIP2 binding sites in IKs channel activation and identifies a compound (CA1) that selectively modulates IKs, offering a potential mechanism for specific antiarrhythmic drug development.
The I Ks channel, composed of voltage-gated potassium channel KCNQ1 and regulatory subunit KCNE1, controls cardiac action potential durations. KCNQ1 and I Ks activation requires PIP 2 , and its depletion abolishes channel opening. KCNQ1 adopts both bent and straight conformations and can bind two PIP 2 molecules: one adjacent to VSD (V-PIP 2 ), and the other at the VSD-pore interface (C-PIP 2 ). Here we show that the two PIP 2 perform essential yet distinct roles: V-PIP 2 enables the bent-to-straight transition, whereas C-PIP 2 mediates VSD-pore coupling. VSD activation elevates the V-PIP 2 site, permitting the shift from the bent, intermediate open (IO) state associated with KCNQ1 to the straight, I Ks -exclusive activated open (AO) state, which is further stabilized by C-PIP 2 . Leveraging this mechanism, we develop a compound CA1, which selectively targets the V-PIP 2 site and modulates I Ks channel activity without affecting KCNQ1, offering a promising conceptional path for specific and safe antiarrhythmic therapeutics.
Zhao et al. (Wed,) conducted a other in Cardiac IKs potassium channel function. CA1 compound was evaluated on IKs channel activity and conformational changes. Two PIP2 molecules perform distinct roles in IKs channel activation: V-PIP2 enables the bent-to-straight transition, whereas C-PIP2 mediates VSD-pore coupling, a mechanism selectively targeted by compound CA1.
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