ArticleProceedings of the National Academy of Sciences of the United States of America2004
RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 211 papers.
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Who cites it
211 citing papers in PubMed, 433 citations in OpenAlex.
- Trial
- Pleiotropic Phenotype of RYR2 Exon 3 Deletion: Biventricular Noncompaction and Malignant Arrhythmias.JACC. Case reports · 2026Article
- Catecholaminergic polymorphic ventricular tachycardia-linked ryanodine receptor variants exhibit domain-specific calcium leak and calmodulin affinity properties.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
- TRIC-A Loss Sensitizes the Heart to β-Adrenergic Stress and Drives Cardiomyocyte Death and Fibrosis.Biomolecules · 2026Article
- Potentiation of ryanodine receptor-mediated calcium release by MAPK is responsible for epidermal transformation and carcinogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- Catecholaminergic polymorphic ventricular tachycardia: A narrative review of recent advances in genetics, mechanisms, diagnosis, and treatment.Asian heart journal · 2025Review
- Novel Ca2+ wave mechanisms in cardiac myocytes revealed by multiscale Ca2+ release model.The Journal of general physiology · 2025Article
- Catecholaminergic Polymorphic Ventricular Tachycardia: Advancing From Molecular Insights to Preclinical Models.Journal of the American Heart Association · 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
- S-nitrosylation of cardiac myocyte proteins may underlie sex differences in cardiac disease.Frontiers in physiology · 2025Review
- Article
- Gain-of-Function and Loss-of-Function Mutations in the RyR2-Expressing Gene Are Responsible for the CPVT1-Related Arrhythmogenic Activities in the Heart.Current issues in molecular biology · 2024Article
- The Role of Human-Induced Pluripotent Stem Cells in Studying Cardiac Channelopathies.International journal of molecular sciences · 2024Review
- p38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia.Nature cardiovascular research · 2023Article
- Blocking p38γ/δ, a molecular cardiac defibrillator.Nature cardiovascular research · 2023Article
- Calmodulin Mutations in Human Disease.Channels (Austin, Tex.) · 2023Review
- Clustering properties of the cardiac ryanodine receptor in health and heart failure.Journal of molecular and cellular cardiology · 2023Review
- Study of amphipathic metabolites in cardiac pathophysiology: Insights gained from long-chain acylcarnitines and calcium handling.Journal of cellular and molecular medicine · 2023Article
151 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
The cardiac ryanodine receptor (RyR2) governs the release of Ca2+ from the sarcoplasmic reticulum, which initiates muscle contraction. Mutations in RyR2 have been linked to ventricular tachycardia (VT) and sudden death, but the precise molecular mechanism is unclear. It is known that when the sarcoplasmic reticulum store Ca2+ content reaches a critical level, spontaneous Ca2+ release occurs, a process we refer to as store-overload-induced Ca2+ release (SOICR). In view of the well documented arrhythmogenic nature of SOICR, we characterized the effects of disease-causing RyR2 mutations on SOICR in human embryonic kidney (HEK)293 cells and found that, at elevated extracellular Ca2+ levels, HEK293 cells expressing RyR2 displayed SOICR in a manner virtually identical to that observed in cardiac cells. Using this cell model, we demonstrated that the RyR2 mutations linked to VT and sudden death, N4104K, R4496C, and N4895D, markedly increased the occurrence of SOICR. At the molecular level, we showed that these RyR2 mutations increased the sensitivity of single RyR2 channels to activation by luminal Ca2+ and enhanced the basal level of [3H]ryanodine binding. We conclude that disease-causing RyR2 mutations, by enhancing RyR2 luminal Ca2+ activation, reduce the threshold for SOICR, which in turn increases the propensity for triggered arrhythmia. Abnormal RyR2 luminal Ca2+ activation likely contributes to the enhanced SOICR commonly observed in various cardiac conditions, including heart failure, and may represent a unifying mechanism for Ca2+ overload-associated VT.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.