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

Jeffrey Abrams, Daniel Roybal, Nourdine Chakouri, Alexander N. Katchman, 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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

Original languageEnglish (US)
Article numbere141736
JournalJCI Insight
Volume5
Issue number19
DOIs
StatePublished - Oct 2 2020

Funding

We thank Ben Haeffele and Po Wei Kang for the automated leak subtraction algorithm. This publication was supported by R01 HL140934 to SOM, 1R01NS110672 to MBJ, and 1R01HL152236 to EYW. Images were collected and analyzed in the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University, supported by NIH grant P30 CA013696 (National Cancer Institute). Daniel Roybal was supported by T32 HL120826 and F31 HL142178. Jessica Hennessey was supported by T32 HL007854. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels'. Together they form a unique fingerprint.

Cite this