ArticleThe Journal of biological chemistry2015
Arrhythmogenic Calmodulin Mutations Affect the Activation and Termination of Cardiac Ryanodine Receptor-mediated Ca2+ Release.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 67 citations in OpenAlex.
- Drafting the calmodulation playbook: Emerging structural insights into transient receptor potential channel regulation by calmodulin.The Journal of physiology · 2026Review
- Structural and Functional Regulation of RyR2 in Cardiac Calcium Handling and Arrhythmogenesis.Biomedicines · 2026Review
- Calmodulin D133H Disrupts CaCells · 2025Article
- Arrhythmia-Associated Calmodulin E105A Mutation Alters the Binding Affinity of CaM to a Ryanodine Receptor 2 CaM-Binding Pocket.International journal of molecular sciences · 2023Article
- Sex and Gene Influence Arrhythmia Susceptibility in Murine Models of Calmodulinopathy.Circulation. Arrhythmia and electrophysiology · 2023Article
- Long QT syndrome-associated calmodulin variants disrupt the activity of the slowly activating delayed rectifier potassium channel.The Journal of physiology · 2023Article
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.International journal of molecular sciences · 2023Article
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.bioRxiv : the preprint server for biology · 2023Article
- Human calmodulin mutations cause arrhythmia and affect neuronal function in C. elegans.Human molecular genetics · 2023Article
- Role of CaArchives of toxicology · 2023Review
- Calmodulin mutations affecting Gly114 impair binding to the NaFrontiers in pharmacology · 2023Article
- Binding and Functional Folding (BFF): A Physiological Framework for Studying Biomolecular Interactions and Allostery.Journal of molecular biology · 2022Review
- Engineered CaM2 modulates nuclear calcium oscillation and enhances legume root nodule symbiosis.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- CPVT-associated calmodulin variants N53I and A102V dysregulate Ca2+ signalling via different mechanisms.Journal of cell science · 2022Article
- Calmodulin variants associated with congenital arrhythmia impair selectivity for ryanodine receptors.Frontiers in molecular biosciences · 2022Article
- Physiologically Relevant Free CaJournal of molecular biology · 2021Article
- Mechanistic link between CaM-RyR2 interactions and the genesis of cardiac arrhythmia.Biophysical journal · 2021Article
- The Crystal Structure of Calmodulin Bound to the Cardiac Ryanodine Receptor (RyR2) at Residues Phe4246-Val4271 Reveals a Fifth Calcium Binding Site.Biochemistry · 2021Article
- Infanticide vs. inherited cardiac arrhythmias.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 · 2021Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
The intracellular Ca(2+) sensor calmodulin (CaM) regulates the cardiac Ca(2+) release channel/ryanodine receptor 2 (RyR2), and mutations in CaM cause arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome. Here, we investigated the effect of CaM mutations causing CPVT (N53I), long QT syndrome (D95V and D129G), or both (CaM N97S) on RyR2-mediated Ca(2+) release. All mutations increased Ca(2+) release and rendered RyR2 more susceptible to store overload-induced Ca(2+) release (SOICR) by lowering the threshold of store Ca(2+) content at which SOICR occurred and the threshold at which SOICR terminated. To obtain mechanistic insights, we investigated the Ca(2+) binding of the N- and C-terminal domains (N- and C-domain) of CaM in the presence of a peptide corresponding to the CaM-binding domain of RyR2. The N53I mutation decreased the affinity of Ca(2+) binding to the N-domain of CaM, relative to CaM WT, but did not affect the C-domain. Conversely, mutations N97S, D95V, and D129G had little or no effect on Ca(2+) binding to the N-domain but markedly decreased the affinity of the C-domain for Ca(2+). These results suggest that mutations D95V, N97S, and D129G alter the interaction between CaM and the CaMBD and thus RyR2 regulation. Because the N53I mutation minimally affected Ca(2+) binding to the C-domain, it must cause aberrant regulation via a different mechanism. These results support aberrant RyR2 regulation as the disease mechanism for CPVT associated with CaM mutations and shows that CaM mutations not associated with CPVT can also affect RyR2. A model for the CaM-RyR2 interaction, where the Ca(2+)-saturated C-domain is constitutively bound to RyR2 and the N-domain senses increases in Ca(2+) concentration, is proposed.
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