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

Po Wei Kang; Annie M Westerlund; Jingyi Shi; Kelli McFarland White; Alex K Dou; Amy H Cui; Jonathan R Silva; Lucie Delemotte; Jianmin Cui

doi:10.1126/sciadv.abd6798

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

Sci Adv. 2020 Dec 11;6(50):eabd6798. doi: 10.1126/sciadv.abd6798. Print 2020 Dec.

Authors

Po Wei Kang¹, Annie M Westerlund², Jingyi Shi¹, Kelli McFarland White¹, Alex K Dou¹, Amy H Cui¹, Jonathan R Silva¹, Lucie Delemotte³, Jianmin Cui⁴

Affiliations

¹ Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity, and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA.
² Department of Applied Physics, KTH Royal Institute of Technology, Science for Life Laboratory, Stockholm, Sweden.
³ Department of Applied Physics, KTH Royal Institute of Technology, Science for Life Laboratory, Stockholm, Sweden. jcui@wustl.edu lucie.delemotte@scilifelab.se.
⁴ Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity, and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA. jcui@wustl.edu lucie.delemotte@scilifelab.se.

Abstract

Calmodulin (CaM) and phosphatidylinositol 4,5-bisphosphate (PIP₂) are potent regulators of the voltage-gated potassium channel KCNQ1 (K_V7.1), which conducts the cardiac I _Ks current. Although cryo-electron microscopy 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. This leads to conformational changes that alter VSD-pore coupling to stabilize open states. 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 physiological function.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Abstract

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