ArticleThe Journal of clinical investigation2008
Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice.
Article in The Journal of clinical investigation, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 211 papers, 1 of them a synthesis that pooled it.
What it found
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Who cites it
211 citing papers in PubMed, 1 synthesis or guideline pooled it, 403 citations in OpenAlex.
- Systematic Review of the Genetics of Sudden Unexpected Death in Epilepsy: Potential Overlap With Sudden Cardiac Death and Arrhythmia-Related Genes.Journal of the American Heart Association · 2020Pooled it
- Multitarget Drug Design for Cardiovascular Disease: Bridging Chemistry and Medicine.ChemMedChem · 2026Review
- 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
- Ryanodine receptor 2 mutations in catecholaminergic polymorphic ventricular tachycardia: From molecular mechanisms to precision medicine.World journal of cardiology · 2026Review
- Conventional Antiarrhythmics Class I-IV, Late INa Inhibitors, IKs Enhancers, RyR2 Stabilizers, Gap Junction Modulators, Atrial-Selective Antiarrhythmics, and Stable Gastric Pentadecapeptide BPC 157 as Useful Cytoprotective Therapy in Arrhythmias.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Unraveling SUDEP: Mechanisms of Seizure-Induced Cardiac and Respiratory Impairment.Epilepsy currents · 2026Article
- Beyond cardiac risk factors: non-cardiovascular comorbidities in sudden cardiac death prediction.Frontiers in cardiovascular medicine · 2026Review
- Abnormal calcium release and delayed afterdepolarizations: A comparison of two mathematical models for human ventricular myocytes.PloS one · 2026Article
- Cryo-EM Brings the Mechanisms of Activation, Inactivation, and Inhibition of Ryanodine Receptors into Focus.Advances in experimental medicine and biology · 2026Review
- Article
- RYR2 Variants in Catecholaminergic Polymorphic Ventricular Tachycardia Patients: Insights From Protein Structure and Clinical Data.Circulation. Arrhythmia and electrophysiology · 2025Review
- Catecholaminergic polymorphic ventricular tachycardia: A narrative review of recent advances in genetics, mechanisms, diagnosis, and treatment.Asian heart journal · 2025Review
- Article
- Heritability of sudden cardiac death in Thoroughbred racehorses.Equine veterinary journal · 2025Article
- Whole exome sequencing revealed ultra-rare genetic variations in juvenile myoclonic epilepsy.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- Treatment Outcomes in Children With Catecholaminergic Polymorphic Ventricular Tachycardia: A Single Institutional Experience.Korean circulation journal · 2024Article
- Dual calcium-voltage optical mapping of regional voltage and calcium signals in intact murineJournal of molecular and cellular cardiology plus · 2024Article
- Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.Nature neuroscience · 2024Article
- Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.medRxiv : the preprint server for health sciences · 2024Article
151 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death.
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Registered trials
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.