Next Article in Journal
Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease
Next Article in Special Issue
The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities
Previous Article in Journal
Selective Gold Recovery from Homogenous Aqueous Solutions Containing Gold and Platinum Ions by Aromatic Amino Acid-Containing Peptides
Previous Article in Special Issue
GABAA Receptor/STEP61 Signaling Pathway May Be Involved in Emulsified Isoflurane Anesthesia in Rats
Article

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

1
Department of Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
2
Division of Neurology, The Children’s Hospital of Philadelphia, Abramson Research Center, Room 512C-D, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
3
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
4
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
6
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
7
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)
Background: Genetic variants in voltage-gated sodium channels (Nav) encoded by SCNXA genes, responsible for INa, and Kv4.3 channels encoded by KCND3, responsible for the transient outward current (Ito), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that Kv4.3 and Nav variants regulate each other’s function, thus modulating INa/Ito balance in cardiomyocytes and INa/I(A) balance in neurons. Methods: Bicistronic and other constructs were used to express WT or variant Nav1.5 and Kv4.3 channels in HEK293 cells. INa and Ito were recorded. Results: SCN5A variants associated with BrS reduced INa, but increased Ito. Moreover, BrS and SCA19/22 KCND3 variants associated with a gain of function of Ito, significantly reduced INa, whereas the SCA19/22 KCND3 variants associated with a loss of function (LOF) of Ito significantly increased INa. Auxiliary subunits Navβ1, MiRP3 and KChIP2 also modulated INa/Ito 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 Kv4.3 cell-surface expression. Conclusion: Nav and Kv4.3 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; Nav1.5; SCN5A; Kv4.3; KCND3; SCN1A; Nav1.1; channelopathies arrhythmia; Brugada syndrome; spinocerebellar ataxia; Nav1.5; SCN5A; Kv4.3; KCND3; SCN1A; Nav1.1; channelopathies
Show Figures

Graphical abstract

MDPI and ACS Style

Clatot, J.; Neyroud, N.; Cox, R.; Souil, C.; Huang, J.; Guicheney, P.; Antzelevitch, C. Inter-Regulation of Kv4.3 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 Kv4.3 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 Kv4.3 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

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop