PIP2 activation of the cardiac IKs potassium channel

Lu Zhao; Xianjin Xu; Chenxi Cui; Rui Duan; Ali A Kermani; Jingyi Shi; Lu Han; Ji Sun; Xiaoqin Zou; Jianmin Cui

doi:10.1038/s41467-026-74123-8

PIP₂ activation of the cardiac I_Ks potassium channel

Nat Commun. 2026 Jun 10. doi: 10.1038/s41467-026-74123-8. Online ahead of print.

Authors

Lu Zhao^#¹, Xianjin Xu^#^{2

3

4

5}, Chenxi Cui^#⁶, Rui Duan^#^{2

3

4

5}, Ali A Kermani⁶, Jingyi Shi¹, Lu Han¹, Ji Sun⁷, Xiaoqin Zou^{8

9

10

11}, Jianmin Cui¹²

Affiliations

¹ Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO, USA.
² Department of Physics and Astronomy, University of Missouri, Columbia, MO, USA.
³ Department of Biochemistry, University of Missouri, Columbia, MO, USA.
⁴ Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
⁵ Institute for Data Science and Informatics, University of Missouri, Columbia, MO, USA.
⁶ Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
⁷ Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA. ji.sun@stjude.org.
⁸ Department of Physics and Astronomy, University of Missouri, Columbia, MO, USA. zoux@missouri.edu.
⁹ Department of Biochemistry, University of Missouri, Columbia, MO, USA. zoux@missouri.edu.
¹⁰ Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA. zoux@missouri.edu.
¹¹ Institute for Data Science and Informatics, University of Missouri, Columbia, MO, USA. zoux@missouri.edu.
¹² Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO, USA. jcui@wustl.edu.

^# Contributed equally.

PMID: 42270663
DOI: 10.1038/s41467-026-74123-8

Abstract

The I_Ks channel, composed of voltage-gated potassium channel KCNQ1 and regulatory subunit KCNE1, controls cardiac action potential durations. KCNQ1 and I_Ks 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, I_Ks-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 I_Ks channel activity without affecting KCNQ1, offering a promising conceptional path for specific and safe antiarrhythmic therapeutics.

Abstract

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