Regulation of the cardiac Na+ channel NaV1.5 by post-translational modifications.
The cardiac voltage-gated Na(+) channel, Na(V)1.5, is responsible for the upstroke of the action potential in cardiomyocytes and for efficient propagation of the electrical impulse in the myocardium. Even subtle alterations of Na(V)1.5 function, as caused by mutations in its gene SCN5A, may lead to many different arrhythmic phenotypes in carrier patients. In addition, acquired malfunctions of Na(V)1.5 that are secondary to cardiac disorders such as heart failure and cardiomyopathies, may also play significant roles in arrhythmogenesis. While it is clear that the regulation of Na(V)1.5 protein expression and function tightly depends on genetic mechanisms, recent studies have demonstrated that Na(V)1.5 is the target of various post-translational modifications that are pivotal not only in physiological conditions, but also in disease. In this review, we examine the recent literature demonstrating glycosylation, phosphorylation by Protein Kinases A and C, Ca(2+)/Calmodulin-dependent protein Kinase II, Phosphatidylinositol 3-Kinase, Serum- and Glucocorticoid-inducible Kinases, Fyn and Adenosine Monophosphate-activated Protein Kinase, methylation, acetylation, redox modifications, and ubiquitylation of Na(V)1.5. Modern and sensitive mass spectrometry approaches, applied directly to channel proteins that were purified from native cardiac tissues, have enabled the determination of the precise location of post-translational modification sites, thus providing essential information for understanding the mechanistic details of these regulations. The current challenge is first, to understand the roles of these modifications on the expression and the function of Na(V)1.5, and second, to further identify other chemical modifications. It is postulated that the diversity of phenotypes observed with Na(V)1.5-dependent disorders may partially arise from the complex post-translational modifications of channel protein components.
L'institut du thorax, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1087, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6291, Université de Nantes, Nantes, France. Electronic address: celine.marionneau@univ-nantes.fr.
Céline
C
Marionneau
Department of Clinical Research, University of Bern, Bern, Switzerland. Electronic address: Hugues.Abriel@dkf.unibe.ch.
Hugues
H
Abriel
D000107:Acetylation; D000818:Animals; D005786:Gene Expression Regulation; D006031:Glycosylation; D006801:Humans; D013058:Mass Spectrometry; D008745:Methylation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D040901:Proteomics / Q000379:methods; D054875:Ubiquitination
D062554:NAV1.5 Voltage-Gated Sodium Channel
Arrhythmias; Cardiac Na(V)1.5 channels; Native proteomics; Post-translational modifications