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The α-subunit of the cardiac voltage-gated sodium channel (Na_V1.5) plays a central role in cardiomyocyte excitability. We have recently reported that Na_V1.5 is post-translationally modified by arginine methylation. Here, we aimed to identify the enzymes that methylate Na_V1.5, and to describe the role of arginine methylation on Na_V1.5 function. Our results show that protein arginine methyl transferase (PRMT)-3 and -5 methylate Na_V1.5 in vitro, interact with Na_V1.5 in human embryonic kidney (HEK) cells, and increase Na_V1.5 current density by enhancing Na_V1.5 cell surface expression. Our observations are the first evidence of regulation of a voltage-gated ion channel, including calcium, potassium, sodium and TRP channels, by arginine methylation.