The Cardiac Sodium Channel Is Post-Translationally Modified by Arginine Methylation

The α subunit of the cardiac sodium channel (Nav1.5) is an essential protein in the initial depolarization phase of the cardiomyocyte action potential. Post-translational modifications such as phosphorylation are known to regulate Nav1.5 function. Here, we used a proteomic approach for the study of the post-translational modifications of Nav1.5 using tsA201 cells as a model system. We generated a stable cell line expressing Nav1.5, purified the sodium channel, and analyzed Nav1.5 by MALDI-TOF and LC–MS/MS. We report the identification of arginine methylation as a novel post-translational modification of Nav1.5. R513, R526, and R680, located in the linker between domains I and II in Nav1.5, were found in mono- or dimethylated states. The functional relevance of arginine methylation in Nav1.5 is underscored by the fact that R526H and R680H are known Nav1.5 mutations causing Brugada and long QT type 3 syndromes, respectively. Our work describes for the first time arginine methylation in the voltage-gated ion channel superfamily.