ArticleCirculation research2014
Divergent regulation of ryanodine receptor 2 calcium release channels by arrhythmogenic human calmodulin missense mutants.
Article in Circulation research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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Who cites it
85 citing papers in PubMed, 152 citations in OpenAlex.
- Metabolic stress exacerbates CaExperimental physiology · 2026Article
- Calmodulin mutation N54I causes autosomal dominant CPVT in mice.bioRxiv : the preprint server for biology · 2026Article
- Catecholaminergic polymorphic ventricular tachycardia-linked ryanodine receptor variants exhibit domain-specific calcium leak and calmodulin affinity properties.The Journal of physiology · 2026Article
- Calmodulinopathy variants impair CaV1.3 and CaV2.1 regulation.The Journal of general physiology · 2026Article
- Dynamic-Structure Redesign of Calmodulin Reveals Mechanistic Constraints on Ryr2 Regulation.bioRxiv : the preprint server for biology · 2026Article
- Drafting the calmodulation playbook: Emerging structural insights into transient receptor potential channel regulation by calmodulin.The Journal of physiology · 2026Review
- APD restitution controls arrhythmia emergence in cardiac tissue with RyR2 dysfunction.The Journal of physiology · 2026Article
- Calmodulin D133H Disrupts CaCells · 2025Article
- Enrichment of mutant calmodulin protein in a murine model of a human calmodulinopathy.JCI insight · 2025Article
- Distinct intracellular spatiotemporal expression of Calmodulin genes underlies functional diversity of Calmodulin-dependent signalling in cardiac myocytes.Cardiovascular research · 2025Article
- Quantification of Sarcoplasmic Reticulum CaCurrent protocols · 2024Article
- Antisense Oligonucleotide Therapy for Calmodulinopathy.Circulation · 2024Article
- Kinetics and mapping of Ca-driven calmodulin conformations on skeletal and cardiac muscle ryanodine receptors.Nature communications · 2024Article
- Molecular Pathways and Animal Models of Arrhythmias.Advances in experimental medicine and biology · 2024Article
- Early-onset cardiac arrest, prolonged QT interval, and left ventricular hypertrophy: Phenotypic manifestations of a pathogenic de novo calmodulin variant.HeartRhythm case reports · 2023Article
- Calmodulin Mutations in Human Disease.Channels (Austin, Tex.) · 2023Review
- Arrhythmia-associated calmodulin variants interact with KCNQ1 to confer aberrant membrane trafficking and function.PNAS nexus · 2023Article
- 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
- RyR2 Binding of an Antiarrhythmic Cyclic Depsipeptide Mapped Using Confocal Fluorescence Lifetime Detection of FRET.ACS chemical biology · 2023Article
- Sex and Gene Influence Arrhythmia Susceptibility in Murine Models of Calmodulinopathy.Circulation. Arrhythmia and electrophysiology · 2023Article
25 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
rationaleCalmodulin (CaM) mutations are associated with an autosomal dominant syndrome of ventricular arrhythmia and sudden death that can present with divergent clinical features of catecholaminergic polymorphic ventricular tachycardia (CPVT) or long QT syndrome (LQTS). CaM binds to and inhibits ryanodine receptor (RyR2) Ca release channels in the heart, but whether arrhythmogenic CaM mutants alter RyR2 function is not known.
objectiveTo gain mechanistic insight into how human CaM mutations affect RyR2 Ca channels. METHODS AND
resultsWe studied recombinant CaM mutants associated with CPVT (N54I and N98S) or LQTS (D96V, D130G, and F142L). As a group, all LQTS-associated CaM mutants (LQTS-CaMs) exhibited reduced Ca affinity, whereas CPVT-associated CaM mutants (CPVT-CaMs) had either normal or modestly lower Ca affinity. In permeabilized ventricular myocytes, CPVT-CaMs at a physiological intracellular concentration (100 nmol/L) promoted significantly higher spontaneous Ca wave and spark activity, a typical cellular phenotype of CPVT. Compared with wild-type CaM, CPVT-CaMs caused greater RyR2 single-channel open probability and showed enhanced binding affinity to RyR2. Even a 1:8 mixture of CPVT-CaM:wild-type-CaM activated Ca waves, demonstrating functional dominance. In contrast, LQTS-CaMs did not promote Ca waves and exhibited either normal regulation of RyR2 single channels (D96V) or lower RyR2-binding affinity (D130G and F142L). None of the CaM mutants altered Ca/CaM binding to CaM-kinase II.
conclusionsA small proportion of CPVT-CaM is sufficient to evoke arrhythmogenic Ca disturbances, whereas LQTS-CaMs do not. Our findings explain the clinical presentation and autosomal dominant inheritance of CPVT-CaM mutations and suggest that RyR2 interactions are unlikely to explain arrhythmogenicity of LQTS-CaM mutations.
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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.