FGF13 is a Regulator of the Cardiac Voltage-Gated Sodium Channel Nav1.5

The four members of the intracellular Fibroblast Growth Factor (iFGF) subfamily, FGF11-14, regulate voltage-gated sodium (Nav) channels. A missense mutation in FGF14 causes spinocerebellar ataxia 27, thought to be due to Nav channel dysfunction. iFGFs are expressed in the heart, but whether they regulate cardiac Nav channels is not known. Using quantitative real-time RT-PCR, we identified that FGF13 isoforms are the dominant iFGFs in adult mouse heart. Using whole cell patch-clamp configuration, we determined a functional link between FGF13 and Nav1.5. We found that the FGF13 isoforms, FGF13S, FGF13U, and FGF13VY differentially modulate Nav1.5 current density when transiently co-expressed in HEK293 cells. Steady-state activation was not altered. In contrast, steady-state availability was significantly shifted towards the depolarizing direction by each of the FGF13 isoforms. Most strikingly, FGF13S induced a dramatic slowing of recovery from inactivation. Co-immunoprecipitation showed that FGF13 interacted with Nav1.5 in cardiomyocytes. Using a pull down assay, we found that FGF13 directly interacted with C-terminus of Nav1.5. Immunostaining showed that FGF13 co-localized with Nav1.5 on sarcolemma. Some FGF13 is present in subcellular regions devoid of Nav1.5, suggesting other roles than sodium channel modulation. FGF13 knockdown by adenoviral infection with shRNA in adult mice cardiomyocytes affected sodium current density and steady-state availability. FGF13 knockdown in a neonatal rat cardiomyocyte monolayer reduced cardiac impulse conduction and the velocity of the action potential upstroke. These data are the first report of FGF13 as regulator of Nav1.5 in heart and suggest that FGF13 isoform-specific regulation of cardiac Nav channels plays important physiological and pathophysiological roles.