ArticleJournal of molecular and cellular cardiology2013
Caveolin-3 suppresses late sodium current by inhibiting nNOS-dependent S-nitrosylation of SCN5A.
Article in Journal of molecular and cellular cardiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 81 citations in OpenAlex.
- Identification and functional analysis of a new putative caveolin-3 variant found in a patient with sudden unexplained death.Journal of biomedical science · 2014Trial
- Protein S-Nitrosylation in Heart Failure: A Compartment-Resolved Review of Mechanisms, Evidence Boundaries, and Translational Perspectives.Antioxidants (Basel, Switzerland) · 2026Review
- S-Nitrosylation in Cardiovascular Disorders: The State of the Art.Biomolecules · 2025Review
- Voltage-Gated Sodium Channels: A Therapeutic Target in Ischemic Heart Disease.Reviews in cardiovascular medicine · 2025Review
- Review
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model.PloS one · 2024Article
- Caveolin-3 and Caveolae regulate ventricular repolarization.Journal of molecular and cellular cardiology · 2023Article
- Role of CaArchives of toxicology · 2023Review
- Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced NaMilitary Medical Research · 2022Article
- Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current.Nature cardiovascular research · 2022Article
- Caveolin-3 and Arrhythmias: Insights into the Molecular Mechanisms.Journal of clinical medicine · 2022Review
- Late Sodium Current of the Heart: Where Do We Stand and Where Are We Going?Pharmaceuticals (Basel, Switzerland) · 2022Review
- Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias.International journal of molecular sciences · 2022Review
- Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.Clinical and translational medicine · 2021Review
- Review
- Nitrosative Stress and Human Disease: Therapeutic Potential of Denitrosylation.International journal of molecular sciences · 2021Review
- Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation.Stem cell reports · 2021Article
- Nitric oxide down-regulates voltage-gated NaScientific reports · 2021Article
- Long QT syndrome - Bench to bedside.Heart rhythm O2 · 2021Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
aimsMutations in CAV3-encoding caveolin-3 (Cav3) have been implicated in type 9 long QT syndrome (LQT9) and sudden infant death syndrome (SIDS). When co-expressed with SCN5A-encoded cardiac sodium channels these mutations increased late sodium current (INa) but the mechanism was unclear. The present study was designed to address the mechanism by which the LQT9-causing mutant Cav3-F97C affects the function of caveolar SCN5A. METHODS AND
resultsHEK-293 cells expressing SCN5A and LQT9 mutation Cav3-F97C resulted in a 2-fold increase in late INa compared to Cav3-WT. This increase was reversed by the neural nitric oxide synthase (nNOS) inhibitor L-NMMA. Based on these findings, we hypothesized that an nNOS complex mediated the effect of Cav3 on SCN5A. A SCN5A macromolecular complex was established in HEK-293 cells by transiently expressing SCN5A, α1-syntrophin (SNTA1), nNOS, and Cav3. Compared with Cav3-WT, Cav3-F97C produced significantly larger peak INa amplitudes, and showed 3.3-fold increase in the late INa associated with increased S-nitrosylation of SCN5A. L-NMMA reversed both the Cav3-F97C induced increase in late and peak INa and decreased S-nitrosylation of SCN5A. Overexpression of Cav3-F97C in adult rat cardiomyocytes caused a significant increase in late INa compared to Cav3-WT, and prolonged the action potential duration (APD90) in a nNOS-dependent manner.
conclusionsCav3 is identified as an important negative regulator for cardiac late INa via nNOS dependent direct S-nitrosylation of SCN5A. This provides a molecular mechanism for how Cav3 mutations increase late INa to cause LQT9. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".
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