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 bySCNXAgenes, responsible for I-Na, and K(v)4.3 channels encoded byKCND3, 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:SCN5Avariants associated with BrS reduced I-Na, but increased I-to. Moreover, BrS and SCA19/22KCND3variants associated with a gain of function of I-to, significantly reduced I-Na, whereas the SCA19/22KCND3variants associated with a loss of function (LOF) of I(to)significantly increased I-Na. Auxiliary subunits Na-v beta 1, 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 LOFSCN5Avariants 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.