Inter-Regulation of K(v)4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies

Background: Genetic variants in voltage-gated sodium channels (Na(v)) encoded by SCNXA genes, responsible for I(Na), and K(v)4.3 channels encoded by KCND3, responsible for the transient outward current (I(to)), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that K(v)4.3 and Na(v) variants regulate each other’s function, thus modulating I(Na)/I(to) balance in cardiomyocytes and I(Na)/I((A)) balance in neurons. Methods: Bicistronic and other constructs were used to express WT or variant Na(v)1.5 and K(v)4.3 channels in HEK293 cells. I(Na) and I(to) were recorded. Results: SCN5A variants associated with BrS reduced I(Na), but increased I(to). Moreover, BrS and SCA19/22 KCND3 variants associated with a gain of function of I(to), significantly reduced I(Na), whereas the SCA19/22 KCND3 variants associated with a loss of function (LOF) of I(to) significantly increased I(Na). Auxiliary subunits Na(v)β1, MiRP3 and KChIP2 also modulated I(Na)/I(to) balance. Co-immunoprecipitation and Duolink studies suggested that the two channels interact within the intracellular compartments and biotinylation showed that LOF SCN5A variants can increase K(v)4.3 cell-surface expression. Conclusion: Na(v) and K(v)4.3 channels modulate each other’s function via trafficking and gating mechanisms, which have important implications for improved understanding of these allelic cardiac and neuronal syndromes.