Fibroblast Growth Factor Homologous Factors are Important Modulators of Cardiac Ion Channels

Abstract

Fibroblast growth factor (FGF) homologous factors (FHFs, FGF11-14) are a family of FGFs that are not secreted, nor activate FGF receptors. Instead, they remain intracellular and bind to the voltage-gated Na+ channel C-terminus and modulate function. FGF14 is a locus for the neurodegenerative disease spinocerebellar ataxia 27 and the disease has been attributed to decreased neuronal excitability from changes in Na+ channel function. However, several lines of evidence, including data from heterologous expression systems and the distribution of FGF13 within the ventricular cardiomyocyte suggested that it also modulates the CaV1.2 voltage-gated Ca2+ channel. The central hypothesis to this study is that FHFs modulate both voltage-gated Na+ and Ca2+ channel channels in the ventricular cardiomyocyte and therefore are loci for cardiac arrhythmia. Using an adult ventricular cardiomyocyte system with adenoviral gene transfer, we manipulated the levels of FGF13 in the cell and performed electrophysiology, biochemistry and immunocytochemistry to analyze the effects on voltage-gated Ca2+ channel channel localization and function. We showed that FGF13 is in complex with Junctophilin-2 and modulates CaV1.2 current density and localization to the t-tubule, leading to changes in Ca2+ channel-induced Ca2+ channel release and ultimately a shortened ventricular action potential. Through collaboration with the Mayo Clinic, a mutation in FGF12, the most highly expressed FHF in human ventricle was found in a patient with Brugada syndrome. Using similar methodology, we determined that this mutation results specifically in a NaV1.5 loss of function without affecting CaV1.2 function, resulting in a Brugada-like ventricular action potential. This data shows that FHFs are potent modulators of multiple ion channels and novel arrhythmogenic loci.