The sodium channel NaX: Possible player in excitation–contraction coupling
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 06, 2020
- Source ID
- 10.1002/iub.2247
Entities
People
- Alfred L. George Jr.
- Elena Bogdanovic
- Franck Potet
- Hari S Iyer
- John Andrew Wasserstrom
- Kai P. Leung
- Robert Galiano
- Seok J. Hong
- Thomas A. Mustoe
- William Marszalec
Organizations
- National Heart, Lung, and Blood Institute
- Northwestern University
- Oak Ridge Institute for Science and Education
- United States Army Institute of Surgical Research
- United States Army Medical Research and Development Command
- United States Department of Energy