The sodium channel NaX: Possible player in excitation–contraction coupling

Elena Bogdanovic*, Franck Potet, William Marszalec, Hari Iyer, Robert Galiano, Seok J. Hong, Kai P. Leung, John Andrew Wasserstrom, Alfred L. George, Thomas A. Mustoe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The sodium channel NaX (encoded by the SCN7A gene) was originally identified in the heart and skeletal muscle and is structurally similar to the other voltage-gated sodium channels but does not appear to be voltage gated. Although NaX is expressed at high levels in cardiac and skeletal muscle, little information exists on the function of NaX in these tissues. Transcriptional profiling of ion channels in the heart in a subset of patients with Brugada syndrome revealed an inverse relationship between the expression of NaX and NaV1.5 suggesting that, in cardiac myocytes, the expression of these channels may be linked. We propose that NaX plays a role in excitation–contraction coupling based on our experimental observations. Here we show that in cardiac myocytes, NaX is expressed in a striated pattern on the sarcolemma in regions corresponding to the sarcomeric M-line. Knocking down NaX expression decreased NaV1.5 mRNA and protein and reduced the inward sodium current (INa+) following cell depolarization. When the expression of NaV1.5 was knocked down, ~85% of the INa+ was reduced consistent with the observations that NaV1.5 is the main voltage-gated sodium channel in cardiac muscle and that NaX likely does not directly participate in mediating the INa+ following depolarization. Silencing NaV1.5 expression led to significant upregulation of NaX mRNA. Similar to NaV1.5, NaX protein levels were rapidly downregulated when the intracellular [Ca2+] was increased either by CaCl2 or caffeine. These data suggest that a relationship exists between NaX and NaV1.5 and that NaX may play a role in excitation–contraction coupling.

Original languageEnglish (US)
Pages (from-to)601-606
Number of pages6
JournalIUBMB Life
Volume72
Issue number4
DOIs
StatePublished - Apr 1 2020

Keywords

  • Ca
  • M-line
  • Na
  • Na1.5
  • SCN5A
  • SCN7A
  • cardiac myocytes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Clinical Biochemistry
  • Cell Biology

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