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

Po Wei Kang, Annie M. Westerlund, Jingyi Shi, Kelli Mc Farland White, Alex K. Dou, Amy H. Cui, Jonathan R. Silva, Lucie Delemotte, Jianmin Cui

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Calmodulin (CaM) and phosphatidylinositol 4,5-bisphosphate (PIP2) are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the cardiac IKs 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.

Original languageEnglish
Article numbereabd6798
JournalScience Advances
Issue number50
StatePublished - Dec 11 2020


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