Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels.

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE
    • Publication Information:
      Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-
    • Subject Terms:
      Action Potentials* ; Mutation*; Arrhythmias, Cardiac/*pathology ; Calmodulin/*metabolism ; Fibroblast Growth Factors/*metabolism ; Myocytes, Cardiac/*pathology ; NAV1.5 Voltage-Gated Sodium Channel/*metabolism; Animals ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/metabolism ; Calcium Signaling ; Calmodulin/genetics ; Female ; Fibroblast Growth Factors/genetics ; Humans ; Male ; Mice ; Mice, Transgenic ; Myocytes, Cardiac/metabolism ; NAV1.5 Voltage-Gated Sodium Channel/genetics ; Protein Binding ; Sodium/metabolism
    • 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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    • Grant Information:
      T32 HL120826 United States HL NHLBI NIH HHS; R01 HL113136 United States HL NHLBI NIH HHS; R01 HL126735 United States HL NHLBI NIH HHS; R01 NS110672 United States NS NINDS NIH HHS; R01 HL146149 United States HL NHLBI NIH HHS; P30 CA013696 United States CA NCI NIH HHS; T32 HL007854 United States HL NHLBI NIH HHS; T32 HL160520 United States HL NHLBI NIH HHS; R01 HL152236 United States HL NHLBI NIH HHS; R01 HL140934 United States HL NHLBI NIH HHS; F31 HL142178 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: Arrhythmias; Calmodulin; Cardiology; Sodium channels
    • Accession Number:
      0 (Calmodulin)
      0 (NAV1.5 Voltage-Gated Sodium Channel)
      62031-54-3 (Fibroblast Growth Factors)
      9NEZ333N27 (Sodium)
    • Publication Date:
      Date Created: 20200902 Date Completed: 20210609 Latest Revision: 20240202
    • Publication Date:
      20240202
    • Accession Number:
      PMC7566708
    • Accession Number:
      10.1172/jci.insight.141736
    • Accession Number:
      32870823