Do sodium channel proteolytic fragments regulate sodium channel expression?. Issue 5 (3rd September 2017)

• Record Type: Journal Article
• Authors: Onwuli, Donatus O.; Yañez-Bisbe, Laia; Pinsach-Abuin, Mel·lina; Tarradas, Anna; Brugada, Ramon; Greenman, John; Pagans, Sara; Beltran-Alvarez, Pedro
• Is Part Of: Channels. Volume 11:Issue 5(2017)
• Page Start: 476
• Page End: 481
• Publication Date: 2017-09-03
• Subjects: gene expression -- mutagenesis -- nuclear localization signal -- transcription factor -- voltage-gated sodium channel; Ion channels -- Periodicals; 572.3
• DOI: 10.1080/19336950.2017.1355663
• Languages: English
• ISSNs: 1933-6950

Abstract

ABSTRACT: The cardiac voltage-gated sodium channel (gene: SCN5A, protein: NaV 1.5) is responsible for the sodium current that initiates the cardiomyocyte action potential. Research into the mechanisms of SCN5A gene expression has gained momentum over the last few years. We have recently described the transcriptional regulation of SCN5A by GATA4 transcription factor. In this addendum to our study, we report our observations that 1) the linker between domains I and II (LDI-DII ) of NaV 1.5 contains a nuclear localization signal (residues 474–481) that is necessary to localize LDI-DII into the nucleus, and 2) nuclear LDI-DII activates the SCN5A promoter in gene reporter assays using cardiac-like H9c2 cells. Given that voltage-gated sodium channels are known targets of proteases such as calpain, we speculate that NaV 1.5 degradation is signaled to the cell transcriptional machinery via nuclear localization of LDI-DII and subsequent stimulation of the SCN5A promoter.