ArticleJournal of the American Heart Association2014
Arrhythmogenic calmodulin mutations disrupt intracellular cardiomyocyte Ca2+ regulation by distinct mechanisms.
Article in Journal of the American Heart Association, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 95 citations in OpenAlex.
- Calmodulinopathy variants impair CaV1.3 and CaV2.1 regulation.The Journal of general physiology · 2026Article
- Beyond the blueprint: decoding calmodulinopathy-a case report showcasing the utility of multifaceted treatments.European heart journal. Case reports · 2025Article
- The mechanism of LQTS related CaM mutation E141G interfering with CaJournal of physiology and biochemistry · 2025Article
- Antisense Oligonucleotide Therapy for Calmodulinopathy.Circulation · 2024Article
- Calcium- and calmodulin-dependent inhibition of NMDA receptor currents.Biophysical journal · 2024Review
- 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
- 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
- NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling.The Journal of clinical investigation · 2023Article
- Calmodulin mutations affecting Gly114 impair binding to the NaFrontiers in pharmacology · 2023Article
- Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte.Biomolecules · 2022Article
- Basic Research Approaches to Evaluate Cardiac Arrhythmia in Heart Failure and Beyond.Frontiers in physiology · 2022Review
- NaStructure (London, England : 1993) · 2021Article
- Mechanisms underlying pathological CaPflugers Archiv : European journal of physiology · 2021Review
- Predicting Genetic Variation Severity Using Machine Learning to Interpret Molecular Simulations.Biophysical journal · 2021Article
- Article
- Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels.JCI insight · 2020Article
- Biophysical Investigation of Sodium Channel Interaction with β-Subunit Variants Associated with Arrhythmias.Bioelectricity · 2020Article
- Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.The Journal of physiology · 2020Review
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 3 countries.
Funding
Abstract
backgroundCalmodulin (CaM) mutations have been identified recently in subjects with congenital long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT), but the mechanisms responsible for these divergent arrhythmia-susceptibility syndromes in this context are unknown. We tested the hypothesis that LQTS-associated CaM mutants disrupt Ca2+ homeostasis in developing cardiomyocytes possibly by affecting either late Na current or Ca2+-dependent inactivation of L-type Ca2+ current. METHODS AND
resultsWe coexpressed CaM mutants with the human cardiac Na channel (NaV1.5) in tsA201 cells, and we used mammalian fetal ventricular cardiomyocytes to investigate LQTS- and CPVT-associated CaM mutations (LQTS- and CPVT-CaM). LQTS-CaM mutants do not consistently affect L-type Na current in heterologous cells or native cardiomyocytes, suggesting that the Na channel does not contribute to LQTS pathogenesis in the context of CaM mutations. LQTS-CaM mutants (D96V, D130G, F142L) impaired Ca2+-dependent inactivation, whereas the CPVT-CaM mutant N54I had no effect on Ca2+-dependent inactivation. LQTS-CaM mutants led to loss of Ca2+-transient entrainment with the rank order from greatest to least effect: CaM-D130G~CaM-D96V>>CaM-F142L. This rank order follows measured Ca2+-CaM affinities for wild-type and mutant CaM. Acute isoproterenol restored entrainment for CaM-130G and CaM-D96V but caused irreversible cytosolic Ca2+ overload for cells expressing a CPVT-CaM mutant.
conclusionsCaM mutations associated with LQTS may not affect L-type Na+ current but may evoke defective Ca2+-dependent inactivation of L-type Ca2+ current.
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