Protein arginine methyl transferases-3 and -5 increase cell surface expression of cardiac sodium channel

• Published in: FEBS letters 2013-10, Vol.587 (19), p.3159-3165
• Main Authors: Beltran-Alvarez, Pedro, Espejo, Alexsandra, Schmauder, Ralf, Beltran, Carlos, Mrowka, Ralf, Linke, Thomas, Batlle, Montserrat, Pérez-Villa, Félix, Pérez, Guillermo J., Scornik, Fabiana S., Benndorf, Klaus, Pagans, Sara, Zimmer, Thomas, Brugada, Ramon
• Format: Article
• Language: English
• Subjects: action potential; Arginine methylation; ArgMe; beats per minute; bmp; cardiac isoform of the voltage-gated sodium channel α subunit; Cell Membrane - metabolism; Cells, Cultured; CFP or YFP; co-immunoprecipitation; co-IP; cyan or yellow fluorescent protein; Fluorescence Resonance Energy Transfer; FRET; Förster resonance energy transfer; HEK; human embryonic kidney; Humans; immunoprecipitation; Ion channel; linker between domains DI and DII of NaV1.5; LI–II; Myocardium - metabolism; NaV1.5; NAV1.5 Voltage-Gated Sodium Channel - metabolism; Patch-Clamp Techniques; Post-translational modification; PRMT; protein arginine methyltransferase; Protein-Arginine N-Methyltransferases - metabolism; S-(5′-adenosyl)-l-methionine; SAM; Sodium channel
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2013.07.043

•We identify the protein arginine methyl transferases (PRMT) that methylate NaV1.5.•We describe the effect of PRMT on NaV1.5 function.•PRMT3 and PRMT5 increase NaV1.5 cell surface expression.•This is the first report showing that PRMT regulate a voltage-gated ion channel. The α-subunit of the cardiac voltage-gated sodium channel (NaV1.5) plays a central role in cardiomyocyte excitability. We have recently reported that NaV1.5 is post-translationally modified by arginine methylation. Here, we aimed to identify the enzymes that methylate NaV1.5, and to describe the role of arginine methylation on NaV1.5 function. Our results show that protein arginine methyl transferase (PRMT)-3 and -5 methylate NaV1.5 in vitro, interact with NaV1.5 in human embryonic kidney (HEK) cells, and increase NaV1.5 current density by enhancing NaV1.5 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. PRMT5physically interacts with Nav1.5 by fluorescent resonance energy transfer (View interaction) PRMT3physically interacts with Nav1.5 by fluorescent resonance energy transfer (View interaction) Nav1.5physically interacts with PRMT3 by anti tag coimmunoprecipitation (View interaction) PRMT1physically interacts with Nav1.5 by fluorescent resonance energy transfer (View interaction) Nav1.5physically interacts with PRMT1 by anti tag coimmunoprecipitation (View interaction)