Elementary mechanisms of calmodulin regulation of Na <sub>V</sub> 1.5 producing divergent arrhythmogenic phenotypes
Po Wei Kang, Nourdine Chakouri, Johanna Diaz, Gordon F. Tomaselli, David T. Yue, Manu Ben‐Johny
Abstract
Significance Calmodulin (CaM) regulation of cardiac Na V channels is vital for cardiac physiology and pathophysiology. Channelopathic mutations in Na V 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 syndrome stems from a loss-of-channel function. Yet, mechanisms that elicit seemingly paradoxical changes in channel function are unknown. Using single-channel analysis, we demonstrate that the disruption of CaM binding to Na V 1.5 diminishes channel activity and enhances the propensity for persistent Na + current, all resulting from a switch in the Na V inactivation mechanism. These findings reveal insights into the mechanism of CaM regulation of Na V channels as well as inform upon alterations in channel function that trigger life-threatening arrhythmias.