ArticleThe Journal of biological chemistry2009
Functional Interactions between Distinct Sodium Channel Cytoplasmic Domains through the Action of Calmodulin.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 2 of them syntheses that pooled it.
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Who cites it
53 citing papers in PubMed, 2 syntheses or guidelines pooled it, 83 citations in OpenAlex.
- Calmodulation meta-analysis: predicting calmodulin binding via canonical motif clustering.The Journal of general physiology · 2014Pooled it
- Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.Nature genetics · 2010Pooled it
- An all-atom model of the human cardiac sodium channel in a lipid bilayer.Scientific reports · 2024Article
- Biophysical mechanisms of myocardium sodium channelopathies.Pflugers Archiv : European journal of physiology · 2024Review
- Nernst-Planck-Gaussian finite element modelling of CaFrontiers in physiology · 2024Article
- Feedback contributions to excitation-contraction coupling in native functioning striated muscle.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- Complete heart block associated with paraneoplastic hypercalcemia: a case report.European heart journal. Case reports · 2023Article
- Calmodulin mutations affecting Gly114 impair binding to the NaFrontiers in pharmacology · 2023Article
- NaStructure (London, England : 1993) · 2021Article
- Ca2+-dependent modulation of voltage-gated myocyte sodium channels.Biochemical Society transactions · 2021Review
- Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.Clinical and translational medicine · 2021Review
- Calmodulin Interactions with Voltage-Gated Sodium Channels.International journal of molecular sciences · 2021Review
- Finite element analysis predicts CaScientific reports · 2021Article
- Elementary mechanisms of calmodulin regulation of NaProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Properties of Calmodulin Binding to NaNeurochemical research · 2021Article
- Sarcoplasmic reticular CaScientific reports · 2021Article
- Structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation.The Journal of general physiology · 2021Review
- Crystal structures of CaProceedings of the National Academy of Sciences of the United States of America · 2019Article
- Mutations in NaFrontiers in physiology · 2019Article
- The Effect of CaInternational journal of molecular sciences · 2018Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Sodium channels are fundamental signaling molecules in excitable cells, and are molecular targets for local anesthetic agents and intracellular free Ca(2+) ([Ca(2+)](i)). Two regions of Na(V)1.5 have been identified previously as [Ca(2+)](i)-sensitive modulators of channel inactivation. These include a C-terminal IQ motif that binds calmodulin (CaM) in different modes depending on Ca(2+) levels, and an immediately adjacent C-terminal EF-hand domain that directly binds Ca(2+). Here we show that a mutation of the IQ domain (A1924T; Brugada Syndrome) that reduces CaM binding stabilizes Na(V)1.5 inactivation, similarly and more extensively than even reducing [Ca(2+)](i). Because the DIII-DIV linker is an essential structure in Na(V)1.5 inactivation, we evaluated this domain for a potential CaM binding interaction. We identified a novel CaM binding site within the linker, validated its interaction with CaM by NMR spectroscopy, and revealed its micromolar affinity by isothermal titration calorimetry. Mutation of three consecutive hydrophobic residues (Phe(1520)-Ile(1521)-Phe(1522)) to alanines in this CaM-binding domain recapitulated the electrophysiology phenotype observed with mutation of the C-terminal IQ domain: Na(V)1.5 inactivation was stabilized; moreover, mutations of either CaM-binding domain abolish the well described stabilization of inactivation by lidocaine. The direct physical interaction of CaM with the C-terminal IQ domain and the DIII-DIV linker, combined with the similarity in phenotypes when CaM-binding sites in either domain are mutated, suggests these cytoplasmic structures could be functionally coupled through the action of CaM. These findings have bearing upon Na(+) channel function in genetically altered channels and under pathophysiologic conditions where [Ca(2+)](i) impacts cardiac conduction.
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Registered trials
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.