FGF13 modulates the gating properties of the cardiac sodium channel Na_v1.5 in an isoform-specific manner

Abstract

(2016) FGF13 modulates the gating properties of the cardiac sodium channel Na v 1.5 in an isoform-specific manner, Channels, 10:5, 410-420, DOI: 10.1080/19336950.2016 To link to this article: https://doi.org/10. 1080/19336950.2016 ABSTRACT 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, Na V 1.5. Knockdown of FGF13 in cardiomyocytes induces slowed ventricular conduction by altering Na V 1.5 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 Na V 1.5, 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 Na V 1.5 function. We found these three splice variants differentially modulated Na V 1.5 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 closedstate 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 Na V 1.5 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 Na V 1.5 channel modulation and suggested the importance of isoform-specific regulation.

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

“…Studies of inducible pluripotent stem cell–derived differentiated cardiomyocytes may further delineate the role of FGF12 in tuning CaM-deficient Na V 1.5 channels in humans. (b) FHF expression and interactions with Na V 1.5 may be tuned by transcriptional or posttranslation modifications ( 34 , 41 ), which unveils latent CaM-dependent modulation. Perhaps the phenotype of Q1909R becomes manifest only in specific circumstances, which may not be apparent in healthy sedentary laboratory animals.…”

Biophysical mechanisms for QRS- and QTc-interval prolongation in mice with cardiac expression of expanded CUG-repeat RNA

“…Interestingly, FGF13 (or fibroblast growth factor homologous factor-2) splicing is developmentally regulated (Munoz-Sanjuan et al, 2000), and FGF13 transcripts represent the major FGF isoforms expressed in rodent heart (Wang et al, 2011). In particular, interaction of the FGF13S splice isoform with the cardiac Na channel shifts steady-state inactivation to more depolarized potentials and slows both fast inactivation and channel recovery from inactivation (Yang et al, 2016). Importantly, conditional Fgf13 knockout in the heart, which eliminates all FGF13 splice isoforms, reduces maximal AP dV/dt, delays Na channel recovery from fast inactivation, and prolongs the ventricular AP duration (via effects on Ito and IK,slow, but not Iss; Wang et al, 2017).…”

Knockout of the X‐linkedFgf13in the hypothalamic paraventricular nucleus impairs sympathetic output to brown fat and causes obesity

“…We and others have characterized Fgf13 effects on cardiac function (13,14,20,(39)(40)(41), neuronal migration during development (19), epileptogenesis (12), and ion channel trafficking and targeting in the axon initiation segment of cultured hippocampal neurons (42), yet gene ablation studies have not been employed to investigate roles for Fgf13 in metabolism, despite multiple studies reporting differential expression in adipose tissue in response to alterations in diet and in different obesogenic genetic backgrounds (21)(22)(23)(24)(25). To begin to investigate metabolic functions we generated a global Fgf13 knockout mouse model on a C57BL/6J background.…”