ArticleJCI insight2017
RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism.
Article in JCI insight, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 31 citations in OpenAlex.
- Ca2+ signalling in cardiac muscle: the importance of balances.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 · 2026Review
- Compromised repolarization reserve in a murine model of catecholaminergic polymorphic ventricular tachycardia caused by RyR2-R420Q mutation.Journal of molecular and cellular cardiology · 2025Article
- RYR2 Variants in Catecholaminergic Polymorphic Ventricular Tachycardia Patients: Insights From Protein Structure and Clinical Data.Circulation. Arrhythmia and electrophysiology · 2025Review
- Disruption of ventricular activation by subthreshold delayed afterdepolarizations in RyR2-R420Q catecholaminergic polymorphic ventricular tachycardia.Journal of molecular and cellular cardiology plus · 2025Article
- Aging and sinus node dysfunction: mechanisms and future directions.Clinical science (London, England : 1979) · 2025Review
- Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders.Nature communications · 2024Article
- Dual effect of cardiac FKBP12.6 overexpression on excitation-contraction coupling and the incidence of ventricular arrhythmia depending on its expression level.Journal of molecular and cellular cardiology · 2024Article
- The Dysfunction of CaInternational journal of molecular sciences · 2023Review
- Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue.International journal of molecular sciences · 2023Article
- Reduction in Junctophilin 2 Expression in Cardiac Nodal Tissue Results in Intracellular Calcium-Driven Increase in Nodal Cell Automaticity.Circulation. Arrhythmia and electrophysiology · 2023Article
- Heart failure in mice induces a dysfunction of the sinus node associated with reduced CaMKII signaling.The Journal of general physiology · 2022Article
- The Purkinje-myocardial junction is the anatomic origin of ventricular arrhythmia in CPVT.JCI insight · 2022Article
- Increase in CaFrontiers in physiology · 2022Article
- ESC working group on cardiac cellular electrophysiology position paper: relevance, opportunities, and limitations of experimental models for cardiac electrophysiology research.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 · 2021Review
- Local recovery of cardiac calcium-induced calcium release interrogated by ultra-effective, two-photon uncaging of calcium.The Journal of physiology · 2021Article
- Impaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation.Circulation research · 2021Article
- Pharmacologic Approach to Sinoatrial Node Dysfunction.Annual review of pharmacology and toxicology · 2021Review
- RyR2 and Calcium Release in Heart Failure.Frontiers in physiology · 2021Review
- Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of CaCirculation · 2019Article
- Catecholaminergic polymorphic ventricular tachycardia, an update.Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2018Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests syncope or sudden death in children and young adults under stress conditions. CPVT patients often present bradycardia and sino-atrial node (SAN) dysfunction. However, the mechanism remains unclear. We analyzed SAN function in two CPVT families and in a novel knock-in (KI) mouse model carrying the RyR2R420Q mutation. Humans and KI mice presented slower resting heart rate. Accordingly, the rate of spontaneous intracellular Ca2+ ([Ca2+]i) transients was slower in KI mouse SAN preparations than in WT, without any significant alteration in the "funny" current (If ). The L-type Ca2+ current was reduced in KI SAN cells in a [Ca2+]i-dependent way, suggesting that bradycardia was due to disrupted crosstalk between the "voltage" and "Ca2+" clock, and the mechanisms of pacemaking was induced by aberrant spontaneous RyR2- dependent Ca2+ release. This finding was consistent with a higher Ca2+ leak during diastolic periods produced by long-lasting Ca2+ sparks in KI SAN cells. Our results uncover a mechanism for the CPVT-causing RyR2 N-terminal mutation R420Q, and they highlight the fact that enhancing the Ca2+ clock may slow the heart rhythm by disturbing the coupling between Ca2+ and voltage clocks.
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