{"id":1148,"date":"2021-03-22T11:55:54","date_gmt":"2021-03-22T11:55:54","guid":{"rendered":"http:\/\/isomlabmichigan.com\/?p=1148"},"modified":"2021-03-22T11:55:54","modified_gmt":"2021-03-22T11:55:54","slug":"jci-insight","status":"publish","type":"post","link":"https:\/\/isomlabmichigan.com\/index.php\/2021\/03\/22\/jci-insight\/","title":{"rendered":"Sodium channel \u03b21 subunits participate in regulated intramembrane proteolysis-excitation coupling"},"content":{"rendered":"<p>Check out Dr. Bouza&#8217;s article describing a novel role for sodium channel \u03b21 subunits in transcriptional regulation <a href=\"https:\/\/insight.jci.org\/articles\/view\/141776\">here<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel \u03b21 subunits, are linked to human diseases with high risk of sudden death, including developmental and epileptic encephalopathy and cardiac arrhythmia. \u03b21 Subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming \u03b1 subunits. They also participate in cell-cell and cell-matrix adhesion, resulting in intracellular signal transduction, promotion of cell migration, calcium handling, and regulation of cell morphology. Here, we investigated regulated intramembrane proteolysis (RIP) of \u03b21 by BACE1 and \u03b3-secretase and show that \u03b21 subunits are substrates for sequential RIP by BACE1 and \u03b3-secretase, resulting in the generation of a soluble intracellular domain (ICD) that is translocated to the nucleus. Using RNA sequencing, we identified a subset of genes that are downregulated by \u03b21-ICD overexpression in heterologous cells but upregulated in Scn1b-null cardiac tissue, which lacks \u03b21-ICD signaling, suggesting that the \u03b21-ICD may normally function as a molecular brake on gene transcription in vivo. We propose that human disease variants resulting in SCN1B LOF cause transcriptional dysregulation that contributes to altered excitability. Moreover, these results provide important insights into the mechanism of SCN1B-linked channelopathies, adding RIP-excitation coupling to the multifunctionality of sodium channel \u03b21 subunits.<\/p>\n","protected":false},"author":5,"featured_media":1149,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_umich_oidc_access":"","footnotes":""},"categories":[6],"tags":[],"class_list":["post-1148","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-events"],"_links":{"self":[{"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/posts\/1148","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/users\/5"}],"replies":[{"embeddable":true,"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/comments?post=1148"}],"version-history":[{"count":2,"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/posts\/1148\/revisions"}],"predecessor-version":[{"id":1151,"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/posts\/1148\/revisions\/1151"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/media\/1149"}],"wp:attachment":[{"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/media?parent=1148"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/categories?post=1148"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/isomlabmichigan.com\/index.php\/wp-json\/wp\/v2\/tags?post=1148"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}