ArticleThe Journal of general physiology2020
An interaction between the III-IV linker and CTD in NaV1.5 confers regulation of inactivation by CaM and FHF.
Article in The Journal of general physiology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 38 citations in OpenAlex.
- Article
- Calcium interaction with Nav1.5 via FGF12A and CaM binding.bioRxiv : the preprint server for biology · 2026Article
- The NaV1.5 auxiliary subunit FGF13 modulates channels by regulating membrane cholesterol independent of channel binding.The Journal of clinical investigation · 2025Article
- Effects of open-channel blocking peptides in NaBiophysical journal · 2025Article
- Voltage-gated sodium channels in excitable cells as drug targets.Nature reviews. Drug discovery · 2025Review
- Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/NaNature communications · 2025Article
- Determinants of iFGF13-mediated regulation of myocardial voltage-gated sodium (NaV) channels in mouse.The Journal of general physiology · 2023Article
- Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors.The Journal of general physiology · 2023Article
- NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling.The Journal of clinical investigation · 2023Article
- Cryo-EM structure of human voltage-gated sodium channel NaProceedings of the National Academy of Sciences of the United States of America · 2023Article
- When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of NaCells · 2022Review
- Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current.Nature cardiovascular research · 2022Article
- Pharmacologically Targeting the Fibroblast Growth Factor 14 Interaction Site on the Voltage-Gated NaInternational journal of molecular sciences · 2021Article
- Calmodulin Interactions with Voltage-Gated Sodium Channels.International journal of molecular sciences · 2021Review
- Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel NaProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors.JCI insight · 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
- Structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation.The Journal of general physiology · 2021Review
- Development of Allosteric Modulators of Voltage-Gated NaCurrent topics in medicinal chemistry · 2021Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Voltage gated sodium channel (VGSC) activation drives the action potential upstroke in cardiac myocytes, skeletal muscles, and neurons. After opening, VGSCs rapidly enter a non-conducting, inactivated state. Impaired inactivation causes persistent inward current and underlies cardiac arrhythmias. VGSC auxiliary proteins calmodulin (CaM) and fibroblast growth factor homologous factors (FHFs) bind to the channel's C-terminal domain (CTD) and limit pathogenic persistent currents. The structural details and mechanisms mediating these effects are not clear. Building on recently published cryo-EM structures, we show that CaM and FHF limit persistent currents in the cardiac NaV1.5 VGSC by stabilizing an interaction between the channel's CTD and III-IV linker region. Perturbation of this intramolecular interaction increases persistent current and shifts the voltage dependence of steady-state inactivation. Interestingly, the NaV1.5 residues involved in the interaction are sites mutated in the arrhythmogenic long QT3 syndrome (LQT3). Along with electrophysiological investigations of this interaction, we present structural models that suggest how CaM and FHF stabilize the interaction and thereby limit the persistent current. The critical residues at the interaction site are conserved among VGSC isoforms, and subtle substitutions provide an explanation for differences in inactivation among the isoforms.
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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.