Regulation of Cardiac Electrical Activity by Lysine Deacetylation.
– SIRTUIN1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel –
The voltage gated cardiac Na+ channel (Nav1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na+ current (INa) and is vital for cardiac electrical activity. Inherited loss of function mutations in SCN5A are associated with cardiac conduction disorders. Here we show that the SIRTUIN1 lysine deacetylase (SIRT1) stimulates INa and trafficking of Nav1.5 to the plasma membrane via deacetylation of Nav1.5 on lysine 1479 (K1479). Deficiency of cardiac SIRT1 in mice induces K1479 hyperacetylation on Nav1.5, precipitates conduction abnormalities, phenocopies human cardiac arrhythmias associated with loss of function of Nav1.5, and leads to premature death. Therefore, SIRT1-dependent dynamic lysine acetylation of Nav1.5 governs INa, cardiac electrical activity, and cardiac rhythm.