IMR Press / FBL / Volume 27 / Issue 7 / DOI: 10.31083/j.fbl2707209
Open Access Original Research
Trafficking and Gating Cooperation Between Deficient Nav1.5-mutant Channels to Rescue INa
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1 Sorbonne Université, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, UMRS-1166, 75013 Paris, France
2 Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
3 The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
4 Department of Physiology and Cell Biology, Frick Center for Heart Failure and Arrhythmias, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA
*Correspondence: (Jérôme Clatot); (Nathalie Neyroud)
Academic Editor: Sarabjit Mastana
Front. Biosci. (Landmark Ed) 2022, 27(7), 209;
Submitted: 7 January 2022 | Revised: 22 February 2022 | Accepted: 8 March 2022 | Published: 30 June 2022
(This article belongs to the Special Issue Genetics of Cardiovascular Diseases)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: Pathogenic variants in SCN5A, the gene encoding the cardiac Na+ channel α-subunit Nav1.5, result in life-threatening arrhythmias, e.g., Brugada syndrome, cardiac conduction defects and long QT syndrome. This variety of phenotypes is underlied by the fact that each Nav1.5 mutation has unique consequences on the channel trafficking and gating capabilities. Recently, we established that sodium channel α-subunits Nav1.5, Nav1.1 and Nav1.2 could dimerize, thus, explaining the potency of some Nav1.5 pathogenic variants to exert dominant-negative effect on WT channels, either by trafficking deficiency or coupled gating. Objective: The present study sought to examine whether Nav1.5 channels can cooperate, or transcomplement each other, to rescue the Na+ current (INa). Such a mechanism could contribute to explain the genotype-phenotype discordance often observed in family members carrying Na+-channel pathogenic variants. Methods: Patch-clamp and immunocytochemistry analysis were used to investigate biophysical properties and cellular localization in HEK293 cells and rat neonatal cardiomyocytes transfected respectively with WT and 3 mutant channels chosen for their particular trafficking and/or gating properties. Results: As previously reported, the mutant channels G1743R and R878C expressed alone in HEK293 cells both abolished INa, G1743R through a trafficking deficiency and R878C through a gating deficiency. Here, we showed that coexpression of both G1743R and R878C nonfunctioning channels resulted in a partial rescue of INa, demonstrating a cooperative trafficking of Nav1.5 α-subunits. Surprisingly, we also showed a cooperation mechanism whereby the R878C gating-deficient channel was able to rescue the slowed inactivation kinetics of the C-terminal truncated R1860X (ΔCter) variant, suggesting coupled gating. Conclusions: Altogether, our results add to the evidence that Nav channels are able to interact and regulate each other’s trafficking and gating, a feature that likely contributes to explain the genotype-phenotype discordance often observed between members of a kindred carrying a Na+-channel pathogenic variant.

cardiac arrhythmia
Sodium channelopathies
Fig. 1.
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