Elementary mechanisms of calmodulin regulation of Na V 1.5 producing divergent arrhythmogenic phenotypes

• DOI: 10.1073/pnas.2025085118
• Publication Date: 2021-05-21T19:50:29Z
• Authors: Po Wei Kang; Nourdine Chakouri; Johanna Diaz; Gordon F. Tomaselli; David T. Yue; Manu Ben-Johny
• Keywords: Models, Molecular; Protein Conformation, alpha-Helical; 0301 basic medicine; Binding Sites; Patch-Clamp Techniques; Action Potentials; Gene Expression; Arrhythmias, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Kinetics; 03 medical and health sciences; HEK293 Cells; Calmodulin; Mutation; Fluorescence Resonance Energy Transfer; Humans; Calcium; Myocytes, Cardiac; Protein Conformation, beta-Strand; Calcium Signaling; Ion Channel Gating; Protein Binding

Significance Calmodulin (CaM) regulation of cardiac Na V channels is vital for physiology and pathophysiology. Channelopathic mutations in 1.5 that disrupt CaM binding trigger two mechanistically divergent arrhythmia syndromes. Specifically, long QT syndrome 3 results from a gain-of-channel function, while Brugada stems loss-of-channel function. Yet, mechanisms elicit seemingly paradoxical changes channel function are unknown. Using single-channel analysis, we demonstrate the disruption to diminishes activity enhances propensity persistent + current, all resulting switch inactivation mechanism. These findings reveal insights into mechanism as well inform upon alterations life-threatening arrhythmias.