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

Clatot, Jérôme; Neyroud, Nathalie; Cox, Robert; Souil, Charlotte; Huang, Jing; Guicheney, Pascale; Antzelevitch, Charles

doi:10.3390/ijms21145057

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

^1,2,*

^3,4,5

¹,

^3,4,

⁶,

^3,4,5

and

Charles Antzelevitch

^1,7,8

Department of Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA

Division of Neurology, The Children’s Hospital of Philadelphia, Abramson Research Center, Room 512C-D, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA

Team “Genomics and Pathophysiology of Myocardial Diseases”, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, Sorbonne Université, UMR_S1166, F-75013 Paris, France

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Team “Genomics and Pathophysiology of Myocardial Diseases”, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, INSERM, UMR_S1166, F-75013 Paris, France

⁵

Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l’Hôpital, F-75013 Paris, France

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Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA

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Lankenau Heart Institute, Main Line Health System, Wynnewood, PA 19096, USA

⁸

Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19104, USA

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2020, 21(14), 5057; https://doi.org/10.3390/ijms21145057

Received: 10 June 2020 / Revised: 4 July 2020 / Accepted: 10 July 2020 / Published: 17 July 2020

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2020)

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Abstract

Background: Genetic variants in voltage-gated sodium channels (Na_v) encoded by SCNXA genes, responsible for I_Na, and K_v4.3 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_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: 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_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 SCN5A 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. View Full-Text

Keywords: arrhythmia; Brugada syndrome; spinocerebellar ataxia; Na_v1.5; SCN5A; Kv4.3; KCND3; SCN1A; Na_v1.1; channelopathies

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Clatot, J.; Neyroud, N.; Cox, R.; Souil, C.; Huang, J.; Guicheney, P.; Antzelevitch, C. Inter-Regulation of K_v4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies. Int. J. Mol. Sci. 2020, 21, 5057. https://doi.org/10.3390/ijms21145057

AMA Style

Clatot J, Neyroud N, Cox R, Souil C, Huang J, Guicheney P, Antzelevitch C. Inter-Regulation of K_v4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies. International Journal of Molecular Sciences. 2020; 21(14):5057. https://doi.org/10.3390/ijms21145057

Chicago/Turabian Style

Clatot, Jérôme, Nathalie Neyroud, Robert Cox, Charlotte Souil, Jing Huang, Pascale Guicheney, and Charles Antzelevitch. 2020. "Inter-Regulation of K_v4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies" International Journal of Molecular Sciences 21, no. 14: 5057. https://doi.org/10.3390/ijms21145057

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

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