ArticleCirculation research2010
Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor.
Article in Circulation research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed.
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- Metabolic stress exacerbates CaExperimental physiology · 2026Article
- Crosstalk between Ryanodine Receptor 2 Dysfunction and FK506-Binding Proteins in Pulmonary Hypertension.Cardiovascular drugs and therapy · 2026Review
- Catecholaminergic polymorphic ventricular tachycardia-linked ryanodine receptor variants exhibit domain-specific calcium leak and calmodulin affinity properties.The Journal of physiology · 2026Article
- Understanding CPVT pathogenic mechanisms based on mutation location within RyR2: towards personalized medicine?The Journal of physiology · 2026Article
- 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
- Crystal structures of Ryanodine Receptor reveal dantrolene and azumolene interactions guiding inhibitor development.Nature communications · 2025Article
- Catecholaminergic polymorphic ventricular tachycardia: A narrative review of recent advances in genetics, mechanisms, diagnosis, and treatment.Asian heart journal · 2025Review
- Prognostic relevance of baseline exercise stress test in RYR2-related CPVT.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 · 2025Article
- Concomitant Administration of Dantrolene is Sufficient to Protect Against Doxorubicin-Induced Cardiomyopathy.JACC. CardioOncology · 2025Article
- Stem cell models of inherited arrhythmias.Nature cardiovascular research · 2024Review
- The proarrhythmogenic role of autonomics and emerging neuromodulation approaches to prevent sudden death in cardiac ion channelopathies.Cardiovascular research · 2024Review
- Catecholaminergic Polymorphic Ventricular Tachycardia: Multiple Clinical Presentations of a Genetically Determined Disease.Journal of clinical medicine · 2023Article
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.International journal of molecular sciences · 2023Article
- RyR2 inhibition with dantrolene is antiarrhythmic, prevents further pathological remodeling, and improves cardiac function in chronic ischemic heart disease.Journal of molecular and cellular cardiology · 2023Article
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.bioRxiv : the preprint server for biology · 2023Article
- Arrhythmogenic mechanism of a novel ryanodine receptor mutation underlying sudden cardiac death.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 · 2023Article
- Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats.Biochemistry and biophysics reports · 2023Article
- Correction: "Ryanopathies" and RyR2 dysfunctions: can we further decipher them using in vitro human disease models?Cell death & disease · 2022Article
29 more citing papers are in PubMed but not listed here.
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15 authors.
Funding
Abstract
rationaleCatecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in a well-defined region of the cardiac type 2 ryanodine receptor (RyR)2. However, the underlying mechanism by which a single mutation in such a large molecule produces drastic effects on channel function remains unresolved.
objectiveUsing a knock-in (KI) mouse model with a human CPVT-associated RyR2 mutation (R2474S), we investigated the molecular mechanism by which CPVT is induced by a single point mutation within the RyR2. METHODS AND
resultsThe R2474S/+ KI mice showed no apparent structural or histological abnormalities in the heart, but they showed clear indications of other abnormalities. Bidirectional or polymorphic ventricular tachycardia was induced after exercise on a treadmill. The interaction between the N-terminal (amino acids 1 to 600) and central (amino acids 2000 to 2500) domains of the RyR2 (an intrinsic mechanism to close Ca(2+) channels) was weakened (domain unzipping). On protein kinase A-mediated phosphorylation of the RyR2, this domain unzipping further increased, resulting in a significant increase in the frequency of spontaneous Ca(2+) transients. cAMP-induced aberrant Ca(2+) release events (Ca(2+) sparks/waves) occurred at much lower sarcoplasmic reticulum Ca(2+) content as compared to the wild type. Addition of a domain-unzipping peptide, DPc10 (amino acids 2460 to 2495), to the wild type reproduced the aforementioned abnormalities that are characteristic of the R2474S/+ KI mice. Addition of DPc10 to the (cAMP-treated) KI cardiomyocytes produced no further effect.
conclusionsA single point mutation within the RyR2 sensitizes the channel to agonists and reduces the threshold of luminal [Ca(2+)] for activation, primarily mediated by defective interdomain interaction within the RyR2.
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