FGF13 modulates the gating properties of the cardiac sodium channel Nav1.5 in an isoform-specific manner.

Published

Journal Article

FGF13 (FHF2), the major fibroblast growth factor homologous factor (FHF) in rodent heart, directly binds to the C-terminus of the main cardiac sodium channel, NaV1.5. Knockdown of FGF13 in cardiomyocytes induces slowed ventricular conduction by altering NaV1.5 function. FGF13 has five splice variants, each of which possess the same core region and C terminus but differing in their respective N termini. Whether and how these alternatively spliced N termini impart isoform-specific regulation of NaV1.5, however, has not been reported. Here, we exploited a heterologous expression to explore the specific modulatory effects of FGF13 splice variants FGF13S, FGF13U and FGF13YV on NaV1.5 function. We found these three splice variants differentially modulated NaV1.5 current density. Although steady-state activation was unaltered by any of the FGF13 isoforms (compared to control cells expressing Nav1.5 but not expressing FGF13), open-state fast inactivation and closed-state fast inactivation were markedly slowed, steady-state availability was significantly shifted toward the depolarizing direction, and the window current was increased by each of FGF13 isoforms. Most strikingly, FGF13S hastened the rate of NaV1.5 entry into the slow inactivation state and induced a dramatic slowing of recovery from inactivation, which caused a large decrease in current after either low or high frequency stimulation. Overall, these data showed the diversity of the roles of the FGF13 N-termini in NaV1.5 channel modulation and suggested the importance of isoform-specific regulation.

Full Text

Duke Authors

Cited Authors

  • Yang, J; Wang, Z; Sinden, DS; Wang, X; Shan, B; Yu, X; Zhang, H; Pitt, GS; Wang, C

Published Date

  • September 2, 2016

Published In

Volume / Issue

  • 10 / 5

Start / End Page

  • 410 - 420

PubMed ID

  • 27246624

Pubmed Central ID

  • 27246624

Electronic International Standard Serial Number (EISSN)

  • 1933-6969

Digital Object Identifier (DOI)

  • 10.1080/19336950.2016.1190055

Language

  • eng

Conference Location

  • United States