{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T06:56:12Z","timestamp":1791615372792,"version":"4.3.4"},"reference-count":44,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:00:00Z","timestamp":1594944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019s 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 Nav\u03b21, 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\u2019s function via trafficking and gating mechanisms, which have important implications for improved understanding of these allelic cardiac and neuronal syndromes.<\/jats:p>","DOI":"10.3390\/ijms21145057","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T06:08:17Z","timestamp":1595225297000},"page":"5057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Inter-Regulation of Kv4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2896-3469","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Clatot","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA"},{"name":"Division of Neurology, The Children\u2019s Hospital of Philadelphia, Abramson Research Center, Room 512C-D, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3382-7680","authenticated-orcid":false,"given":"Nathalie","family":"Neyroud","sequence":"additional","affiliation":[{"name":"Team \u201cGenomics and Pathophysiology of Myocardial Diseases\u201d, Facult\u00e9 de M\u00e9decine Piti\u00e9-Salp\u00eatri\u00e8re, 91 Boulevard de l\u2019H\u00f4pital, Sorbonne Universit\u00e9, UMR_S1166, F-75013 Paris, France"},{"name":"Team \u201cGenomics and Pathophysiology of Myocardial Diseases\u201d, Facult\u00e9 de M\u00e9decine Piti\u00e9-Salp\u00eatri\u00e8re, 91 Boulevard de l\u2019H\u00f4pital, INSERM, UMR_S1166, F-75013 Paris, France"},{"name":"Institute of Cardiometabolism and Nutrition, ICAN, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, 47-83 Boulevard de l\u2019H\u00f4pital, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Souil","sequence":"additional","affiliation":[{"name":"Team \u201cGenomics and Pathophysiology of Myocardial Diseases\u201d, Facult\u00e9 de M\u00e9decine Piti\u00e9-Salp\u00eatri\u00e8re, 91 Boulevard de l\u2019H\u00f4pital, Sorbonne Universit\u00e9, UMR_S1166, F-75013 Paris, France"},{"name":"Team \u201cGenomics and Pathophysiology of Myocardial Diseases\u201d, Facult\u00e9 de M\u00e9decine Piti\u00e9-Salp\u00eatri\u00e8re, 91 Boulevard de l\u2019H\u00f4pital, INSERM, UMR_S1166, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7663-2050","authenticated-orcid":false,"given":"Pascale","family":"Guicheney","sequence":"additional","affiliation":[{"name":"Team \u201cGenomics and Pathophysiology of Myocardial Diseases\u201d, Facult\u00e9 de M\u00e9decine Piti\u00e9-Salp\u00eatri\u00e8re, 91 Boulevard de l\u2019H\u00f4pital, Sorbonne Universit\u00e9, UMR_S1166, F-75013 Paris, France"},{"name":"Team \u201cGenomics and Pathophysiology of Myocardial Diseases\u201d, Facult\u00e9 de M\u00e9decine Piti\u00e9-Salp\u00eatri\u00e8re, 91 Boulevard de l\u2019H\u00f4pital, INSERM, UMR_S1166, F-75013 Paris, France"},{"name":"Institute of Cardiometabolism and Nutrition, ICAN, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, 47-83 Boulevard de l\u2019H\u00f4pital, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7349-1582","authenticated-orcid":false,"given":"Charles","family":"Antzelevitch","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA"},{"name":"Lankenau Heart Institute, Main Line Health System, Wynnewood, PA 19096, USA"},{"name":"Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.joa.2016.07.002","article-title":"J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge","volume":"32","author":"Antzelevitch","year":"2016","journal-title":"J. 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