ArticleJCI insight2019
Ryanodine receptor-bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Ryanodine receptor 2 mutations in catecholaminergic polymorphic ventricular tachycardia: From molecular mechanisms to precision medicine.World journal of cardiology · 2026Review
- Concomitant Administration of Dantrolene is Sufficient to Protect Against Doxorubicin-Induced Cardiomyopathy.JACC. CardioOncology · 2025Article
- Role of type 2 ryanodine receptor stabilisation in autoimmune cell modulation.Advances in rheumatology (London, England) · 2024Article
- Catecholaminergic Polymorphic Ventricular Tachycardia: Clinical Characteristics, Diagnostic Evaluation and Therapeutic Strategies.Journal of clinical medicine · 2024Review
- Calmodulin Mutations in Human Disease.Channels (Austin, Tex.) · 2023Review
- Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats.Biochemistry and biophysics reports · 2023Article
- Review
- Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment.Science advances · 2022Article
- Herpud1 suppress angiotensin II induced hypertrophy in cardiomyocytes.Biochemistry and biophysics reports · 2022Article
- Animal Models to Study Cardiac Arrhythmias.Circulation research · 2022Review
- Structural Insight Into Ryanodine Receptor Channelopathies.Frontiers in pharmacology · 2022Review
- The Ryanodine Receptor as a Sensor for Intracellular Environments in Muscles.International journal of molecular sciences · 2021Review
- Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease.Scientific reports · 2021Article
- Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling.Communications biology · 2020Article
- G790del mutation in DSC2 alone is insufficient to develop the pathogenesis of ARVC in a mouse model.Biochemistry and biophysics reports · 2020Article
- Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure.Expert opinion on therapeutic targets · 2020Review
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in the cardiac type 2 ryanodine receptor (RyR2). Using a knockin (KI) mouse model (R2474S/+), we previously reported that a single point mutation within the RyR2 sensitizes the channel to agonists, primarily mediated by defective interdomain interaction within the RyR2 and subsequent dissociation of calmodulin (CaM) from the RyR2. Here, we examined whether CPVT can be genetically rescued by enhancing the binding affinity of CaM to the RyR2. We first determined whether there is a possible amino acid substitution within the CaM-binding domain in the RyR2 (3584-3603 residues) that can enhance its binding affinity to CaM and found that V3599K substitution showed the highest binding affinity of CaM to the CaM-binding domain. Hence, we generated a heterozygous KI mouse model (V3599K/+) with a single amino acid substitution in the CaM-binding domain of the RyR2 and crossbred it with the heterozygous CPVT-associated R2474S/+-KI mouse to obtain a double-heterozygous R2474S/V3599K-KI mouse model. The CPVT phenotypes - bidirectional or polymorphic ventricular tachycardia, spontaneous Ca2+ transients, and Ca2+ sparks - were all inhibited in the R2474S/V3599K mice. Thus, enhancement of the CaM-binding affinity of the RyR2 is essential to prevent CPVT-associated arrhythmogenesis.
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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.