PIP<sub>2</sub> activation of the cardiac I<sub>Ks</sub> potassium channel.
basic_science · Level V
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- Record sourced from PubMed, PMID 42270663.
- Also identified by DOI 10.1038/s41467-026-74123-8.
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Abstract
The I<sub>Ks</sub> channel, composed of voltage-gated potassium channel KCNQ1 and regulatory subunit KCNE1, controls cardiac action potential durations. KCNQ1 and I<sub>Ks</sub> activation requires PIP<sub>2</sub>, and its depletion abolishes channel opening. KCNQ1 adopts both bent and straight conformations and can bind two PIP<sub>2</sub> molecules: one adjacent to VSD (V-PIP<sub>2</sub>), and the other at the VSD-pore interface (C-PIP<sub>2</sub>). Here we show that the two PIP<sub>2</sub> perform essential yet distinct roles: V-PIP<sub>2</sub> enables the bent-to-straight transition, whereas C-PIP<sub>2</sub> mediates VSD-pore coupling. VSD activation elevates the V-PIP<sub>2</sub> site, permitting the shift from the bent, intermediate open (IO) state associated with KCNQ1 to the straight, I<sub>Ks</sub>-exclusive activated open (AO) state, which is further stabilized by C-PIP<sub>2</sub>. Leveraging this mechanism, we develop a compound CA1, which selectively targets the V-PIP<sub>2</sub> site and modulates I<sub>Ks</sub> channel activity without affecting KCNQ1, offering a promising conceptional path for specific and safe antiarrhythmic therapeutics.