Mutations in NaV1.5 reveal calcium-calmodulin regulation of sodium channel

Eyal Nof, Leonid Vysochek, Eshcar Meisel, Elena Burashnikov, Charles Antzelevitch, Jerome Clatot, Roy Beinart, David Luria, Michael Glikson, Shimrit Oz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Mutations in the SCN5A gene, encoding the cardiac voltage-gated sodium channel NaV1.5, are associated with inherited cardiac arrhythmia and conduction disease. Ca2+-dependent mechanisms and the involvement of β-subunit (NaVβ) in NaV1.5 regulation are not fully understood. A patient with severe sinus-bradycardia and cardiac conduction-disease was genetically evaluated and compound heterozygosity in the SCN5A gene was found. Mutations were identified in the cytoplasmic DIII-IV linker (K1493del) and the C-terminus (A1924T) of NaV1.5, both are putative CaM-binding domains. These mutants were functionally studied in human embryonic kidney (HEK) cells and HL-1 cells using whole-cell patch clamp technique. Calmodulin (CaM) interaction and cell-surface expression of heterologously expressed NaV1.5 mutants were studied by pull-down and biotinylation assays. The mutation K1493del rendered NaV1.5 non-conductive. NaV1.5K1493del altered the gating properties of co-expressed functional NaV1.5, in a Ca2+ and NaVβ1-dependent manner. NaV1.5A1924T impaired NaVβ1-dependent gating regulation. Ca2+-dependent CaM-interaction with NaV1.5 was blunted in NaV1.5K1493del. Electrical charge substitution at position 1493 did not affect CaM-interaction and channel functionality. Arrhythmia and conduction-disease -associated mutations revealed Ca2+-dependent gating regulation of NaV1.5 channels. Our results highlight the role of NaV1.5 DIII-IV linker in the CaM-binding complex and channel function, and suggest that the Ca2+-sensing machinery of NaV1.5 involves NaVβ1.

Original languageEnglish
Article number700
JournalFrontiers in Physiology
Issue numberJUN
StatePublished - 2019


FundersFunder number
Dizengoff Trading Company
Rothschild Caesarea Foundation


    • Calmodulin
    • Cardiac arrhythmia
    • Channelopathies
    • DiII-IV linker
    • Heart
    • SCN5A
    • Sodium current
    • β1-subunit


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