ArticleJournal of molecular and cellular cardiology2014
Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes.
Article in Journal of molecular and cellular cardiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
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Who cites it
102 citing papers in PubMed, 168 citations in OpenAlex.
- Calmodulinopathy variants impair CaV1.3 and CaV2.1 regulation.The Journal of general physiology · 2026Article
- Structural and Functional Regulation of RyR2 in Cardiac Calcium Handling and Arrhythmogenesis.Biomedicines · 2026Review
- Prolonged QT Interval in HIV-1 Infected Humanized Mice Treated Chronically with Dolutegravir/Tenofovir Disoproxil Fumarate/Emtricitabine.International journal of molecular sciences · 2026Article
- Structural differences in Apo-, D132E- and Holo-Calmodulin bound to the IQ domain of the cardiac L-type calcium channel.Molecular simulation · 2026Article
- Functional consequences of calmodulin variants identified among schizophrenia patients and controls.Translational psychiatry · 2025Article
- Calmodulin D133H Disrupts CaCells · 2025Article
- Enrichment of mutant calmodulin protein in a murine model of a human calmodulinopathy.JCI insight · 2025Article
- Casein Kinase 2 Regulates the Intrinsic Activity of L-Type Calcium Currents in Cardiomyocytes.International journal of molecular sciences · 2025Article
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- The mechanism of LQTS related CaM mutation E141G interfering with CaJournal of physiology and biochemistry · 2025Article
- Antisense Oligonucleotide Therapy for Calmodulinopathy.Circulation · 2024Article
- The interaction between neutrophils and atrial myocytes in the occurrence and development of atrial fibrillation.BMC cardiovascular disorders · 2024Article
- Identifying Key Binding Interactions Between the Cardiac L-Type Calcium Channel and Calmodulin Using Molecular Dynamics Simulations.The journal of physical chemistry. B · 2024Article
- Calcium- and calmodulin-dependent inhibition of NMDA receptor currents.Biophysical journal · 2024Review
- Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels.The Journal of general physiology · 2024Article
- Calmodulin Mutations in Human Disease.Channels (Austin, Tex.) · 2023Review
- Early-onset cardiac arrest, prolonged QT interval, and left ventricular hypertrophy: Phenotypic manifestations of a pathogenic de novo calmodulin variant.HeartRhythm case reports · 2023Article
- 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
- Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.European heart journal · 2023Observational
42 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Recent work has identified missense mutations in calmodulin (CaM) that are associated with severe early-onset long-QT syndrome (LQTS), leading to the proposition that altered CaM function may contribute to the molecular etiology of this subset of LQTS. To date, however, no experimental evidence has established these mutations as directly causative of LQTS substrates, nor have the molecular targets of CaM mutants been identified. Here, therefore, we test whether expression of CaM mutants in adult guinea-pig ventricular myocytes (aGPVM) induces action-potential prolongation, and whether affiliated alterations in the Ca(2+) regulation of L-type Ca(2+) channels (LTCC) might contribute to such prolongation. In particular, we first overexpressed CaM mutants in aGPVMs, and observed both increased action potential duration (APD) and heightened Ca(2+) transients. Next, we demonstrated that all LQTS CaM mutants have the potential to strongly suppress Ca(2+)/CaM-dependent inactivation (CDI) of LTCCs, whether channels were heterologously expressed in HEK293 cells, or present in native form within myocytes. This attenuation of CDI is predicted to promote action-potential prolongation and boost Ca(2+) influx. Finally, we demonstrated how a small fraction of LQTS CaM mutants (as in heterozygous patients) would nonetheless suffice to substantially diminish CDI, and derange electrical and Ca(2+) profiles. In all, these results highlight LTCCs as a molecular locus for understanding and treating CaM-related LQTS in this group of patients.
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