PIP2 activation of the cardiac IKs 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 PIP ₂ , and its depletion abolishes channel opening. Previous studies revealed that 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 and stabilizes the straight conformation. Structure-function analysis and molecular dynamic simulations show that VSD activation elevates the V-PIP ₂ 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-PIP ₂ . Leveraging this mechanism, we developed a compound CA1, which selectively targets the V-PIP ₂ site and modulates I _Ks channel activity without affecting KCNQ1, offering a novel and promising conceptional path for specific and safe antiarrhythmic therapeutics.