Ras/Erk signaling is essential for activation of protein synthesis by Gq protein-coupled receptor agonists in adult cardiomyocytes.
The Gq protein-coupled receptor agonists phenylephrine (PE) and endothelin-1 (ET-1) induce cardiac hypertrophy and stimulate protein synthesis in cardiomyocytes. This study aims to investigate how they activate mRNA translation in adult cardiomyocytes. PE and ET-1 do not activate protein kinase B but stimulate Ras and Erk, and their ability to activate protein synthesis was blocked by inhibition of Ras or MEK and by rapamycin, which inhibits mTOR (mammalian target of rapamycin). These agonists activated ribosomal protein S6 kinase 1 (S6K1) and induced phosphorylation of eIF4E-binding protein-1 (4E-BP1) and its release from eIF4E. These effects were blocked by inhibitors of MEK. Furthermore, adenovirus-mediated expression of constitutively-active MEK1 caused activation of S6K1, phosphorylation of 4E-BP1, and activation of protein synthesis in a rapamycin-sensitive manner. Expression of N17Ras inhibited the regulation of S6K1 and protein synthesis by GqPCR agonists. These data point to a signaling pathway involving Ras and MEK that acts, with mTOR, to control regulatory translation factors and activate protein synthesis. This study provides new insights into the mechanisms underlying the stimulation of protein synthesis by hypertrophic agents in heart.
Wang
Lijun
L
Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, Dundee, UK.
Proud
Christopher G
CG
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006321:Heart / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000316:Adrenergic alpha-Agonists; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D010656:Phenylephrine; D011494:Protein Kinases; C546845:mTOR protein, rat; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512963:Rps6ka1 protein, rat; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D018631:ras Proteins; D020123:Sirolimus