ArticleJCI insight2020
Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 31 citations in OpenAlex.
- Targeting Arrhythmogenic Late Sodium Current by FHF1Circulation research · 2026Article
- Nanoscale organization in the cell membrane dynamically modulates the biophysics of voltage-gated sodium channels.Nature communications · 2026Article
- In Vivo Expression of an SCA27A-LinkedThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Article
- 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
- Loss of intracellular FGF14 (iFGF14) increases excitability of mature hippocampal pyramidal neurons.The Journal of general physiology · 2025Article
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- Article
- 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
- Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current.Nature cardiovascular research · 2022Article
- Adrenergic Regulation of Calcium Channels in the Heart.Annual review of physiology · 2022Review
- Calmodulin Interactions with Voltage-Gated Sodium Channels.International journal of molecular sciences · 2021Review
- Use of Proximity Labeling in Cardiovascular Research.JACC. Basic to translational science · 2021Review
- Elementary mechanisms of calmodulin regulation of NaProceedings of the National Academy of Sciences of the United States of America · 2021Article
- CaThe Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias and an absence of increased late Na+ current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human NaV1.5 demonstrated increased late Na+ current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na+ current for the IQ/AA mutant channel, we considered fibroblast growth factor homologous factors (FHFs), which are within the NaV1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing NaV1.5 conjugated to ascorbate peroxidase. We found that FGF13 diminished late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na+ current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na+ current.
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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.