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.