Cicle de conferències 2014-2015. Lecture. How to discover protein post-translational modifications… just by chance

Abstract

The voltage-gated ion channel superfamily consists of 143 proteins and includes the cardiac voltage-gated sodium channel, NaV1.5, which is essential for cardiac excitability. We have uncovered two new modifications of the voltage-gated ion channel superfamily: arginine methylation and N-terminal acetylation.

By chance, we found that R513, R526 and R680 in NaV1.5 are post-translationally methylated. Then, we decided to study this new modification and identified the enzymes responsible for NaV1.5 arginine methylation (PRMT3 and PRMT5). Also, we found that arginine methylation increases NaV1.5 membrane expression. Furthermore, we observed cross-talk between NaV1.5 arginine methylation and phosphorylation of adjacent serine residues. The physiological relevance of NaV1.5 arginine methylation is underscored by the fact that R513H, R526H and R680H are known NaV1.5 mutations causing sudden cardiac death.

Looking for NaV1.5 arginine methylation in human samples of heart failure, we have recently discovered that it is also acetylated at the N-terminus. We are currently investigating the clinical implications of these two novel modifications, with the ultimate goal of describing NaV1.5 arginine methylation and N-terminal acetylation as drivers or markers, and possible pharmacological targets, of cardiac disease.