Inter-Regulation of K_v4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies

• Main Authors: Jérôme Clatot, Nathalie Neyroud, Robert Cox, Charlotte Souil, Jing Huang, Pascale Guicheney, Charles Antzelevitch
• Format: Article
• Language: English
• Published: MDPI AG 2020-07-01
• Series: International Journal of Molecular Sciences
• Subjects: arrhythmia; Brugada syndrome; spinocerebellar ataxia; Na_v1.5; <i>SCN5A</i>; Kv4.3
• Online Access: https://www.mdpi.com/1422-0067/21/14/5057

Background: Genetic variants in voltage-gated sodium channels (Na_v) encoded by <i>SCNXA</i> genes, responsible for I_Na, and K_v4.3 channels encoded by <i>KCND3</i>, 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_v4.3 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_v1.5 and K_v4.3 channels in HEK293 cells. I_Na and I_to were recorded. Results: <i>SCN5A</i> variants associated with BrS reduced I_Na, but increased I_to. Moreover, BrS and SCA19/22 <i>KCND3</i> variants associated with a gain of function of I_to, significantly reduced I_Na, whereas the SCA19/22 <i>KCND3</i> variants associated with a loss of function (LOF) of I_to significantly increased I_Na. Auxiliary subunits Na_vβ1, 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 <i>SCN5A</i> variants can increase K_v4.3 cell-surface expression. Conclusion: Na_v and K_v4.3 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.