ArticleCirculation research2009
Increased Ca2+ sensitivity of the ryanodine receptor mutant RyR2R4496C underlies catecholaminergic polymorphic ventricular tachycardia.
Article in Circulation research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed, 146 citations in OpenAlex.
- Understanding CPVT pathogenic mechanisms based on mutation location within RyR2: towards personalized medicine?The Journal of physiology · 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
- Catecholaminergic polymorphic ventricular tachycardia: A narrative review of recent advances in genetics, mechanisms, diagnosis, and treatment.Asian heart journal · 2025Review
- The proarrhythmogenic role of autonomics and emerging neuromodulation approaches to prevent sudden death in cardiac ion channelopathies.Cardiovascular research · 2024Review
- Transcriptome analysis of effects ofOpen medicine (Warsaw, Poland) · 2024Article
- 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
- How does flecainide impact RyR2 channel function?The Journal of general physiology · 2022Article
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- TECRL deficiency results in aberrant mitochondrial function in cardiomyocytes.Communications biology · 2022Article
- The Purkinje-myocardial junction is the anatomic origin of ventricular arrhythmia in CPVT.JCI insight · 2022Article
- An Optogenetic Arrhythmia Model-Insertion of Several Catecholaminergic Polymorphic Ventricular Tachycardia Mutations IntoFrontiers 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
- Polylactide Nanocapsules Attenuate Adverse Cardiac Cellular Effects of Lyso-7, a Pan-PPAR Agonist/Anti-Inflammatory New Thiazolidinedione.Pharmaceutics · 2021Article
- PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR CaCirculation research · 2021Article
- The oxidation-resistant CaMKII-MM281/282VV mutation does not prevent arrhythmias in CPVT1.Physiological reports · 2021Article
- Impaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation.Circulation research · 2021Article
- Multiphoton Imaging of CaJournal of clinical medicine · 2021Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Cardiac ryanodine receptor (RyR2) mutations are associated with autosomal dominant catecholaminergic polymorphic ventricular tachycardia, suggesting that alterations in Ca(2+) handling underlie this disease. Here we analyze the underlying Ca(2+) release defect that leads to arrhythmia in cardiomyocytes isolated from heterozygous knock-in mice carrying the RyR2(R4496C) mutation. RyR2(R4496C-/-) littermates (wild type) were used as controls. [Ca(2+)](i) transients were obtained by field stimulation in fluo-3-loaded cardiomyocytes and viewed using confocal microscopy. In our basal recording conditions (2-Hz stimulation rate), [Ca(2+)](i) transients and sarcoplasmic reticulum Ca(2+) load were similar in wild-type and RyR2(R4496C) cells. However, paced RyR2(R4496C) ventricular myocytes presented abnormal Ca(2+) release during the diastolic period, viewed as Ca(2+) waves, consistent with the occurrence of delayed afterdepolarizations. The occurrence of this abnormal Ca(2+) release was enhanced at faster stimulation rates and by beta-adrenergic stimulation, which also induced triggered activity. Spontaneous Ca(2+) sparks were more frequent in RyR2(R4496C) myocytes, indicating increased RyR2(R4496C) activity. When permeabilized cells were exposed to different cytosolic [Ca(2+)](i), RyR2(R4496C) showed a dramatic increase in Ca(2+) sensitivity. Isoproterenol increased [Ca(2+)](i) transient amplitude and Ca(2+) spark frequency to the same extent in wild-type and RyR2(R4496C) cells, indicating that the beta-adrenergic sensitivity of RyR2(R4496C) cells remained unaltered. This effect was independent of protein expression variations because no difference was found in the total or phosphorylated RyR2 expression levels. In conclusion, the arrhythmogenic potential of the RyR2(R4496C) mutation is attributable to the increased Ca(2+) sensitivity of RyR2(R4496C), which induces diastolic Ca(2+) release and lowers the threshold for triggered activity.
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