ArticlePflugers Archiv : European journal of physiology2016
The RyR2-P2328S mutation downregulates Nav1.5 producing arrhythmic substrate in murine ventricles.
Article in Pflugers Archiv : European journal of physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 37 citations in OpenAlex.
- Disruption of ventricular activation by subthreshold delayed afterdepolarizations in RyR2-R420Q catecholaminergic polymorphic ventricular tachycardia.Journal of molecular and cellular cardiology plus · 2025Article
- How does flecainide impact RyR2 channel function?The Journal of general physiology · 2022Article
- Clinical Characteristics, Genetic Basis and Healthcare Resource Utilisation and Costs in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia: A Retrospective Cohort Study.Reviews in cardiovascular medicine · 2022Article
- Clinical Characteristics, Genetic Findings and Arrhythmic Outcomes of Patients with Catecholaminergic Polymorphic Ventricular Tachycardia from China: A Systematic Review.Life (Basel, Switzerland) · 2022Review
- Protein Kinase C-Mediated Hyperphosphorylation and Lateralization of Connexin 43 Are Involved in Autoimmune Myocarditis-Induced Prolongation of QRS Complex.Frontiers in physiology · 2022Article
- Ca2+-dependent modulation of voltage-gated myocyte sodium channels.Biochemical Society transactions · 2021Review
- Electrophysiological and Proarrhythmic Effects of Hydroxychloroquine Challenge in Guinea-Pig Hearts.ACS pharmacology & translational science · 2021Article
- Transcriptional profiles of genes related to electrophysiological function in Scn5aPhysiological reports · 2021Article
- Article
- Molecular basis of ventricular arrhythmogenicity in a Pgc-1α deficient murine model.Molecular genetics and metabolism reports · 2021Article
- The conduction velocity-potassium relationship in the heart is modulated by sodium and calcium.Pflugers Archiv : European journal of physiology · 2021Article
- Molecular basis of arrhythmic substrate in ageing murine peroxisome proliferator-activated receptor γ co-activator deficient hearts modelling mitochondrial dysfunction.Bioscience reports · 2019Article
- Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse.Journal of cell science · 2019Article
- Reduced cardiomyocyte NaJournal of cellular physiology · 2019Article
- Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3',5'-adenosine monophosphate (Epac) in murine skeletal muscle.Scientific reports · 2019Article
- Atrial Transcriptional Profiles of Molecular Targets Mediating Electrophysiological Function in Aging andFrontiers in physiology · 2019Article
- Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1βMechanisms of ageing and development · 2018Article
- Multiple targets for flecainide action: implications for cardiac arrhythmogenesis.British journal of pharmacology · 2018Review
- Epac-induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes.Clinical and experimental pharmacology & physiology · 2018Article
- Age-dependent electrocardiographic changes in Pgc-1β deficient murine hearts.Clinical and experimental pharmacology & physiology · 2018Article
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) predisposes to ventricular arrhythmia due to altered Ca(2+) homeostasis and can arise from ryanodine receptor (RyR2) mutations including RyR2-P2328S. Previous reports established that homozygotic murine RyR2-P2328S (RyR2 (S/S)) hearts show an atrial arrhythmic phenotype associated with reduced action potential (AP) conduction velocity and sodium channel (Nav1.5) expression. We now relate ventricular arrhythmogenicity and slowed AP conduction in RyR2 (S/S) hearts to connexin-43 (Cx43) and Nav1.5 expression and Na(+) current (I Na). Stimulation protocols applying extrasystolic S2 stimulation following 8 Hz S1 pacing at progressively decremented S1S2 intervals confirmed an arrhythmic tendency despite unchanged ventricular effective refractory periods (VERPs) in Langendorff-perfused RyR2 (S/S) hearts. Dynamic pacing imposing S1 stimuli then demonstrated that progressive reductions of basic cycle lengths (BCLs) produced greater reductions in conduction velocity at equivalent BCLs and diastolic intervals in RyR2 (S/S) than WT, but comparable changes in AP durations (APD90) and their alternans. Western blot analyses demonstrated that Cx43 protein expression in whole ventricles was similar, but Nav1.5 expression in both whole tissue and membrane fractions were significantly reduced in RyR2 (S/S) compared to wild-type (WT). Loose patch-clamp studies similarly demonstrated reduced I Na in RyR2 (S/S) ventricles. We thus attribute arrhythmogenesis in RyR2 (S/S) ventricles resulting from arrhythmic substrate produced by reduced conduction velocity to downregulated Nav1.5 reducing I Na, despite normal determinants of repolarization and passive conduction. The measured changes were quantitatively compatible with earlier predictions of linear relationships between conduction velocity and the peak I Na of the AP but nonlinear relationships between peak I Na and maximum Na(+) permeability.
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