ArticleFrontiers in pharmacology2015
Mutations in the Voltage Sensors of Domains I and II of Nav1.5 that are Associated with Arrhythmias and Dilated Cardiomyopathy Generate Gating Pore Currents.
Article in Frontiers in pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 54 citations in OpenAlex.
- Article
- The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels.The Journal of general physiology · 2025Article
- Searching for a Solution: A Case Report on Multifocal Ectopic Purkinje-Related Premature Contractions Syndrome.Medicina (Kaunas, Lithuania) · 2025Article
- Mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency.The Journal of general physiology · 2025Article
- The many faces of SCN5A pathogenic variants: from channelopathy to cardiomyopathy.Heart failure reviews · 2025Review
- ELUCIDATING THE DIFFERENTIAL IMPACTS OF EQUIVALENT GATING-CHARGE MUTATIONS IN VOLTAGE-GATED SODIUM CHANNELS.bioRxiv : the preprint server for biology · 2024Article
- Genetic background determines the severity of age-dependent cardiac structural abnormalities and arrhythmia susceptibility in Scn5a-1798insD mice.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 · 2024Article
- Pathogenic gating pore current conducted by autism-related mutations in the NaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Anionic omega currents from single countercharge mutants in the voltage-sensing domain of Ci-VSP.The Journal of general physiology · 2024Article
- Multi-site validation of a functional assay to adjudicatemedRxiv : the preprint server for health sciences · 2023Article
- Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology.Channels (Austin, Tex.) · 2023Review
- Fifty years of gating currents and channel gating.The Journal of general physiology · 2023Review
- Optical measurement of gating pore currents in hypokalemic periodic paralysis model cells.Disease models & mechanisms · 2023Article
- Domain- and state-specific shape of the electric field tunes voltage sensing in voltage-gated sodium channels.Biophysical journal · 2023Article
- Single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with theFrontiers in cardiovascular medicine · 2023Review
- Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes.Frontiers in physiology · 2023Review
- Multifocal ectopic purkinje-related premature contractions and related cardiomyopathy.Frontiers in cardiovascular medicine · 2023Review
- Arrhythmias as Presentation of Genetic Cardiomyopathy.Circulation research · 2022Review
- Racial Disparities in Ion Channelopathies and Inherited Cardiovascular Diseases Associated With Sudden Cardiac Death.Journal of the American Heart Association · 2022Review
- Late Sodium Current of the Heart: Where Do We Stand and Where Are We Going?Pharmaceuticals (Basel, Switzerland) · 2022Review
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5. The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy. Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique. We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods. Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD.
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