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The α subunit of the cardiac voltage-gated sodium channel, Na_V1.5, provides the rapid sodium inward current that initiates cardiomyocyte action potentials. Here, we analyzed for the first time the post-translational modifications of Na_V1.5 purified from end-stage heart failure human cardiac tissue. We identified R526 methylation as the major post-translational modification of any Na_V1.5 arginine or lysine residue. Unexpectedly, we found that the N terminus of Na_V1.5 was: 1) devoid of the initiation methionine, and 2) acetylated at the resulting initial alanine residue. This is the first evidence for N-terminal acetylation in any member of the voltage-gated ion channel superfamily. Our results open the door to explore Na_V1.5 N-terminal acetylation and arginine methylation levels as drivers or markers of end-stage heart failure.