Differential phosphorylation of translation initiation regulators 4EBP1, S6k1, and Erk 1/2 following inhibition of alcohol metabolism in mouse heart.
Acute alcohol intoxication leads to an inhibition of protein synthesis in heart that results in part through altered phosphorylation of protein factors controlling mRNA translation initiation. The purpose of the present set of experiments was designed to examine the effects of inhibitors of ethanol metabolism on the phosphorylation of 4E-binding protein (4EBP1) and S6k1(Thr(389)), two factors regulating mRNA translation initiation. Phosphorylation of 4E-BP1, S6k1(Thr(389)), and Erk 1/2 was reduced 2 h following IP injection of alcohol. Pretreatment with 4-methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase (ADH), did not attenuate the ethanol-induced decrease in phosphorylation of 4EBP1 and S6k1(Thr(389)). In contrast, 4-MP prevented the decrease in Erk 1/2 phosphorylation observed with acute ethanol intoxication. Pretreatment with cyanamide, an inhibitor of aldehyde dehydrogenase, did not attenuate the ethanol-induced decrease in phosphorylation S6k1(Thr(389)), but partially prevented the ethanol-induced lowering of 4EBP1 phosphorylation. The studies indicate that modulation of ethanol metabolism through inhibition of ADH or aldehyde dehydrogenase leads to preferential modulation of the phosphorylation of distinct myocardial signaling systems involved in regulating protein synthesis.
Vary
Thomas C
TC
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Rm C4710, H166, 500 University Drive, Hershey, PA 17033, USA. tvary@psu.edu
Lang
Charles H
CH
D048868:Adaptor Proteins, Signal Transducing; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002492:Central Nervous System Depressants / Q000378:metabolism / Q000633:toxicity*; D003484:Cyanamide / Q000633:toxicity; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D000077604:Fomepizole; D006321:Heart / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D051379:Mice; D008815:Mice, Inbred Strains; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000633:toxicity; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002492:Central Nervous System Depressants; C499527:Eif4ebp1 protein, mouse; D004791:Enzyme Inhibitors; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D011720:Pyrazoles; D000431:Ethanol; D003484:Cyanamide; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D048052:Mitogen-Activated Protein Kinase 3