PIP2 activation of the cardiac IKs potassium channel
Abstract
The IKs channel, composed of voltage-gated potassium channel KCNQ1 and regulatory subunit KCNE1, controls cardiac action potential durations. KCNQ1 and IKs activation requires PIP2, and its depletion abolishes channel opening. 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. VSD activation elevates the V-PIP2 site, permitting the 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 develop a compound CA1, which selectively targets the V-PIP2 site and modulates IKs channel activity without affecting KCNQ1, offering a promising conceptional path for specific and safe antiarrhythmic therapeutics.
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