PIP₂ activation of the cardiac I_Ks potassium channel

The I_Ks channel complex, composed of the voltage-gated potassium channel KCNQ1 and its regulatory subunit KCNE1, is essential for the termination of cardiac action potentials. The function of KCNQ1 and I_Ks requires PIP₂, and its depletion abolishes channel opening. Previous studies revealed that KCNQ1 adopts both bent and straight conformations and can bind two PIP₂ molecules: one adjacent to VSD (V-PIP₂), and the other at the VSD-pore interface (C-PIP₂). Here we show that the two PIP₂ perform essential yet distinct roles: V-PIP₂ enables the bent-to-straight transition, whereas C-PIP₂ mediates VSD-pore coupling and stabilizes the straight conformation. Structure-function analysis and molecular dynamic simulations show that VSD activation elevates the V-PIP₂ site and weakens the CaM-VSD interaction, permitting the conformational 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-PIP₂. Leveraging this mechanism, we developed a compound CA1, which selectively targets the V-PIP₂ site and modulates I_Ks channel activity without affecting KCNQ1, offering a novel and promising conceptional path for specific and safe antiarrhythmic therapeutics.