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bioRxiv · 10.1101/2020.07.04.187161

Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening

Kang, P. W.·Westerlund, A. M.·Shi, J.·McFarland White, K.·Dou, A. K.·Cui, A. H.·Silva, J. R.·Delemotte, L.·Cui, J.
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Abstract

Calmodulin (CaM) and PIP2 are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the IKs current important for repolarization of cardiac action potentials. Although cryo-EM structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully-activated state allows PIP2 to compete with CaM for binding to VSD, leading to the conformational change that alters the VSD-pore coupling. We identify a motif in the KCNQ1 cytosolic domain which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2 and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its function in the heart.Competing Interest StatementJ.S. and J.C. are cofounders of a startup company VivoCor LLC, which is targeting IKs for the treatment of cardiac arrhythmia. The authors declare that they have no other competing interests.View Full Text

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Kang, P. W., Westerlund, A. M., Shi, J., McFarland White, K., Dou, A. K., Cui, A. H., Silva, J. R., Delemotte, L., Cui, J.. 2020-07-04. Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening. https://doi.org/10.1101/2020.07.04.187161

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