title: FGF13 modulates the gating properties of the cardiac sodium channel Nav1.5 in an isoform-specific manner.
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, 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.
authors.affiliation: a Department of Physiology , Hebei Medical University , Shijiazhuang , Hebei , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: b Department of Pharmacology , Hebei Medical University , Shijiazhuang , Hebei , China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: c Department of Medicine/Cardiology and Pharmacology , Ion Channel Research Unit, Duke University Medical Center , Durham , NC , USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Sinden
authors.affiliation: b Department of Pharmacology , Hebei Medical University , Shijiazhuang , Hebei , China.
authors.forename: Xiangchong
authors.initials: X
authors.lastname: Wang
authors.affiliation: b Department of Pharmacology , Hebei Medical University , Shijiazhuang , Hebei , China.
authors.forename: Bin
authors.initials: B
authors.lastname: Shan
authors.affiliation: d Department of Physiology , Shandong University, School of Medicine , Jinan , Shandong , China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: b Department of Pharmacology , Hebei Medical University , Shijiazhuang , Hebei , China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: c Department of Medicine/Cardiology and Pharmacology , Ion Channel Research Unit, Duke University Medical Center , Durham , NC , USA.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
authors.affiliation: b Department of Pharmacology , Hebei Medical University , Shijiazhuang , Hebei , China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; C108111:fibroblast growth factor 13; D005346:Fibroblast Growth Factors
keywords: FGF13; N-termini; Nav1.5; activation; fibroblast growth factor homologous factors; gating; inactivation; isoform; recovery from inactivation; voltage gated sodium channels