ArticleAmerican journal of physiology. Heart and circulatory physiology2011
Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels.
Article in American journal of physiology. Heart and circulatory physiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 49 citations in OpenAlex.
- Late IMedicinal research reviews · 2026Review
- Efficacy of sodium channel blockers in treating myotonia is independent of action potential sodium current block.The Journal of physiology · 2026Article
- Multiscale computational analysis reveals enhanced allosteric modulation of Nav1.5 by dual binding of dapagliflozin and ertugliflozin.Scientific reports · 2025Article
- Biophysical and structural insights into the SCN4A E452K variant linked to myotonia and paramyotonia congenita.Scientific reports · 2025Article
- From genes to clinical management: A comprehensive review of long QT syndrome pathogenesis and treatment.Heart rhythm O2 · 2024Review
- Biophysical mechanisms of myocardium sodium channelopathies.Pflugers Archiv : European journal of physiology · 2024Review
- Structural basis for inhibition of the cardiac sodium channel by the atypical antiarrhythmic drug ranolazine.Nature cardiovascular research · 2023Article
- Coupling the Cardiac Voltage-Gated Sodium Channel to Channelrhodopsin-2 Generates Novel Optical Switches for Action Potential Studies.Membranes · 2022Article
- Novel G1481V and Q1491H SCN5A Mutations Linked to Long QT Syndrome Destabilize the Nav1.5 Inactivation State.CJC open · 2021Article
- Life Cycle of the Cardiac Voltage-Gated Sodium Channel NaFrontiers in physiology · 2020Review
- Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes From Brugada Syndrome Patients With a Loss-of-Function SCN5A Mutation.Frontiers in cell and developmental biology · 2020Article
- Characterization of a novel LQT3 variant with a selective efficacy of mexiletine treatment.Scientific reports · 2019Article
- Protein structure aids predicting functional perturbation of missense variants inComputational and structural biotechnology journal · 2019Article
- The efficacy of Ranolazine on E1784K is altered by temperature and calcium.Scientific reports · 2018Article
- Effect of ovariectomy on intracellular CaAmerican journal of physiology. Heart and circulatory physiology · 2017Article
- Altered physiological functions and ion currents in atrial fibroblasts from patients with chronic atrial fibrillation.Physiological reports · 2016Article
- Review
- Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.Disease models & mechanisms · 2015Article
- Gating pore currents are defects in common with two Nav1.5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy.The Journal of general physiology · 2015Article
- 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.Frontiers in pharmacology · 2015Article
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5 authors at 2 institutions in 2 countries.
Funding
Abstract
Long QT syndrome type 3 (LQT3) has been traced to mutations of the cardiac Na(+) channel (Na(v)1.5) that produce persistent Na(+) currents leading to delayed ventricular repolarization and torsades de pointes. We performed mutational analyses of patients suffering from LQTS and characterized the biophysical properties of the mutations that we uncovered. One LQT3 patient carried a mutation in the SCN5A gene in which the cysteine was substituted for a highly conserved tyrosine (Y1767C) located near the cytoplasmic entrance of the Na(v)1.5 channel pore. The wild-type and mutant channels were transiently expressed in tsA201 cells, and Na(+) currents were recorded using the patch-clamp technique. The Y1767C channel produced a persistent Na(+) current, more rapid inactivation, faster recovery from inactivation, and an increased window current. The persistent Na(+) current of the Y1767C channel was blocked by ranolazine but not by many class I antiarrhythmic drugs. The incomplete inactivation, along with the persistent activation of Na(+) channels caused by an overlap of voltage-dependent activation and inactivation, known as window currents, appeared to contribute to the LQTS phenotype in this patient. The blocking effect of ranolazine on the persistent Na(+) current suggested that ranolazine may be an effective therapeutic treatment for patients with this mutation. Our data also revealed the unique role for the Y1767 residue in inactivating and forming the intracellular pore of the Na(v)1.5 channel.
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