Inter-Regulation of Kv4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue International Journal of Molecular Sciences Année : 2020

Inter-Regulation of Kv4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies

Résumé

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.
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inserm-04021335 , version 1 (09-03-2023)

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Jérôme Clatot, Nathalie Neyroud, Robert Cox, Charlotte Souil, Jing Huang, et al.. Inter-Regulation of Kv4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies. International Journal of Molecular Sciences, 2020, 21, ⟨10.3390/ijms21145057⟩. ⟨inserm-04021335⟩
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