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The α subunit of the cardiac sodium channel (Na_v1.5) is an essential protein in the initial depolarization phase of the cardiomyocyte action potential. Post-translational modifications such as phosphorylation are known to regulate Na_v1.5 function. Here, we used a proteomic approach for the study of the post-translational modifications of Na_v1.5 using tsA201 cells as a model system. We generated a stable cell line expressing Na_v1.5, purified the sodium channel, and analyzed Na_v1.5 by MALDI-TOF and LC–MS/MS. We report the identification of arginine methylation as a novel post-translational modification of Na_v1.5. R513, R526, and R680, located in the linker between domains I and II in Na_v1.5, were found in mono- or dimethylated states. The functional relevance of arginine methylation in Na_v1.5 is underscored by the fact that R526H and R680H are known Na_v1.5 mutations causing Brugada and long QT type 3 …