Do sodium channel proteolytic fragments regulate sodium channel expression?

Onwuli, Donatus O.; Yañez-Bisbe, Laia; Pinsach-Abuin, Mel·lina; Tarradas, Anna; Brugada, Ramon; Greenman, John; Pagans, Sara; Beltran-Alvarez, Pedro

Abstract

© 2017 Taylor & Francis The cardiac voltage-gated sodium channel (gene: SCN5A, protein: Na V 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 (L DI-DII ) of Na V 1.5 contains a nuclear localization signal (residues 474–481) that is necessary to localize L DI-DII into the nucleus, and 2) nuclear L DI-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 Na V 1.5 degradation is signaled to the cell transcriptional machinery via nuclear localization of L DI-DII and subsequent stimulation of the SCN5A promoter.

Citation

Onwuli, D. O., Yañez-Bisbe, L., Pinsach-Abuin, M., Tarradas, A., Brugada, R., Greenman, J., …Beltran-Alvarez, P. (2017). Do sodium channel proteolytic fragments regulate sodium channel expression?. Channels, 11(5), 476-481. https://doi.org/10.1080/19336950.2017.1355663

• Journal Article Type: Article
• Acceptance Date: May 26, 2017
• Online Publication Date: Aug 3, 2017
• Publication Date: Sep 3, 2017
• Deposit Date: Jul 9, 2018
• Publicly Available Date: Jul 11, 2018
• Journal: Channels
• Print ISSN: 1933-6950
• Electronic ISSN: 1933-6969
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 5
• Pages: 476-481
• DOI: https://doi.org/10.1080/19336950.2017.1355663
• Keywords: Voltage-gated sodium channel; Transcription factor; Gene expression; Nuclear localisation signal; Mutagenesis
• Public URL: https://hull-repository.worktribe.com/output/520223
• Publisher URL: https://www.tandfonline.com/doi/full/10.1080/19336950.2017.1355663
• Related Public URLs: https://hydra.hull.ac.uk/resources/hull:15164