Sodium channel b1 subunits are post-translationally modified by tyrosine phosphorylation, S-palmitoylation, and regulated intramembrane proteolysis

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Abstract

Voltage-gated sodium channel (VGSC) b1 subunits are multifunctional proteins that modulate the biophysical properties and cell-surface localization of VGSC a subunits and participate in cell-cell and cell-matrix adhesion, all with important implications for intracellular signal transduction, cell migration, and differentiation. Human loss-of-function variants in SCN1B, the gene encoding the VGSC b1 subunits, are linked to severe diseases with high risk for sudden death, including epileptic encephalopathy and cardiac arrhythmia. We showed previously that b1 subunits are post-translationally modified by tyrosine phosphorylation. We also showed that b1 subunits undergo regulated intramembrane proteolysis via the activity of b-secretase 1 and g-secretase, resulting in the generation of a soluble intracellular domain, b1-ICD, which modulates transcription. Here, we report that b1 subunits are phosphorylated by FYN kinase. Moreover, we show that b1 subunits are S-palmitoylated. Substitution of a single residue in b1, Cys-162, to alanine prevented palmitoylation, reduced the level of b1 polypeptides at the plasma membrane, and reduced the extent of b1-regulated intramembrane proteolysis, suggesting that the plasma membrane is the site of b1 proteolytic processing. Treatment with the clathrin-mediated endocytosis inhibitor, Dyngo-4a, restored the plasma membrane association of b1-p.C162A to WT levels. Despite these observations, palmitoylation-null b1-p. C162A modulated sodium current and sorted to detergent-resistant membrane fractions normally. This is the first demonstration of S-palmitoylation of a VGSC b subunit, establishing precedence for this post-translational modification as a regulatory mechanism in this protein family.

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Bouza, A. A., Philippe, J. M., Edokobi, N., Pinsky, A. M., Offord, J., Calhoun, J. D., … Isom, L. L. (2020). Sodium channel b1 subunits are post-translationally modified by tyrosine phosphorylation, S-palmitoylation, and regulated intramembrane proteolysis. Journal of Biological Chemistry, 295(30), 10380–10393. https://doi.org/10.1074/jbc.ra120.013978

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