PIP2 activation of the cardiac IKs potassium channel

The IKs 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 IKs 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, IKs-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 IKs channel activity without affecting KCNQ1, offering a novel and promising conceptional path for specific and safe antiarrhythmic therapeutics.