Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

• DOI: 10.1172/jci.insight.141736
• Publication Date: 2020-09-01T18:44:32Z
• Authors: Jeffrey Abrams; Daniel Roybal; Nourdine Chakouri; Alexander N. Katc...; Richard Weinberg; Lin Yang; Bi-xing Chen; Sergey I. Zakharov; Jessica A. Hennessey; Uma Mahesh R. Avula; Johanna Diaz; Chaojian Wang; Elaine Y. Wan; Geoffrey S. Pitt; Manu Ben-Johny; Steven O. Marx
• Keywords: Male; 0303 health sciences; Sodium; Cardiology; R; Action Potentials; Arrhythmias, Cardiac; Mice, Transgenic; NAV1.5 Voltage-Gated Sodium Channel; Fibroblast Growth Factors; Mice; 03 medical and health sciences; Calmodulin; Mutation; Medicine; Animals; Humans; Female; Myocytes, Cardiac; Calcium Signaling; Research Article; Protein Binding

The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact vivo remains to be resolved. Here, we identify the role of and NaV1.5 interactome regulating late current cardiomyocytes. We created transgenic mice with cardiac-specific expression human channels alanine substitutions for IQ motif (IQ/AA). mutations rendered incapable binding C-terminus. IQ/AA exhibited normal ventricular repolarization without arrhythmias an absence increased current. In comparison, expressing lidocaine-resistant (F1759A) demonstrated prolonged cardiomyocytes, spontaneous arrhythmias. To determine regulatory factors that prevent mutant channel, considered fibroblast growth factor homologous (FHFs), which are within proteomic subdomain shown by proximity labeling conjugated ascorbate peroxidase. found FGF13 diminished but not F1759A suggesting endogenous FHFs may serve mouse Leveraging mechanisms furnish alternative avenue developing novel pharmacology selectively blunts