ArticleCardiovascular research2012
Dominant-negative effect of SCN5A N-terminal mutations through the interaction of Na(v)1.5 α-subunits.
Article in Cardiovascular research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.
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Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it, 105 citations in OpenAlex.
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- Nanoscale organization in the cell membrane dynamically modulates the biophysics of voltage-gated sodium channels.Nature communications · 2026Article
- Biochemical assessment of α-α-subunit interactions of NaScientific reports · 2026Article
- Short SCN5A Transcript Yields a NaV1.5 Fragment Influencing Cardiac Metabolism.Circulation research · 2026Article
- Clinical profile and prognosis of brugada syndrome SCN5A variant carriers with negative sodium channel blocker challenge.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Article
- Phenotypic Severity ofCirculation. Arrhythmia and electrophysiology · 2026Article
- Parkinson's disease-linked Kir4.2 mutation R28C leads to loss of ion channel function.The Journal of physiology · 2025Article
- Biophysical mechanisms of myocardium sodium channelopathies.Pflugers Archiv : European journal of physiology · 2024Review
- Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families.International journal of molecular sciences · 2024Article
- In silico validation revealed the role of SCN5A mutations and their genotype-phenotype correlations in Brugada syndrome.Molecular genetics & genomic medicine · 2023Article
- Role of the voltage‑gated sodium channel Nav1.6 in glioma and candidate drugs screening.International journal of molecular medicine · 2023Article
- Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes.Frontiers in physiology · 2023Review
- Dominant negative effects of SCN5A missense variants.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- Research progress of Nedd4L in cardiovascular diseases.Cell death discovery · 2022Review
- Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias.International journal of molecular sciences · 2022Review
- Structural Advances in Voltage-Gated Sodium Channels.Frontiers in pharmacology · 2022Review
- Observational
- Review
- Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.Clinical and translational medicine · 2021Review
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11 authors at 4 institutions in 2 countries.
Funding
Abstract
aimsBrugada syndrome (BrS) is an autosomal-inherited cardiac arrhythmia characterized by an ST-segment elevation in the right precordial leads of the electrocardiogram and an increased risk of syncope and sudden death. SCN5A, encoding the cardiac sodium channel Na(v)1.5, is the main gene involved in BrS. Despite the fact that several mutations have been reported in the N-terminus of Na(v)1.5, the functional role of this region remains unknown. We aimed to characterize two BrS N-terminal mutations, R104W and R121W, a construct where this region was deleted, ΔNter, and a construct where only this region was present, Nter. METHODS AND
resultsPatch-clamp recordings in HEK293 cells demonstrated that R104W, R121W, and ΔNter abolished the sodium current I(Na). Moreover, R104W and R121W mutations exerted a strong dominant-negative effect on wild-type (WT) channels. Immunocytochemistry of rat neonatal cardiomyocytes revealed that both mutants were mostly retained in the endoplasmic reticulum and that their co-expression with WT channels led to WT channel retention. Furthermore, co-immunoprecipitation experiments showed that Na(v)1.5-subunits were interacting with each other, even when mutated, deciphering the mutation dominant-negative effect. Both mutants were mostly degraded by the ubiquitin-proteasome system, while ΔNter was addressed to the membrane, and Nter expression induced a two-fold increase in I(Na). In addition, the co-expression of N-terminal mutants with the gating-defective but trafficking-competent R878C-Na(v)1.5 mutant gave rise to a small I(Na).
conclusionThis study reports for the first time the critical role of the Na(v)1.5 N-terminal region in channel function and the dominant-negative effect of trafficking-defective channels occurring through α-subunit interaction.
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