Effects of inhibitors of diacylglycerol metabolism on protein kinase C-mediated responses in hepatocytes.
In hepatocytes pre-labelled with [3H]glycerol, compound R59022 (6-[2-(4-[(4-fluorophenyl)phenylmethylene]-1-piperidinyl)ethyl]-7- methyl-5H-thiazolo[3,2-alpha]pyrimidin-5-one) and 2-bromooctanoate each increased the amount of radioactivity in diacylglycerols. R59022 mimicked the actions of 12-O-tetradecanoylphorbol 13-acetate in completely abolishing the activation by adrenaline (but not that by vasopressin or glucagon) of glycogen phosphorylase a, and in decreasing the activity of glycogen synthetase. Exogenous dioctanoylglycerol caused a small inhibition of adrenaline-stimulated phosphorylase activity. The concentration of R59022 which gave half-maximal inhibition of adrenaline-stimulated phosphorylase activity was 15 microM. Maximal inhibition was observed within 2 min of addition of R59022. 2-Bromooctanoate activated phosphorylase by a process independent of changes in cyclic AMP and Ca2+, and decreased glycogen synthetase. It is concluded that in hepatocytes (i) diacylglycerols which accumulate as a result of the inhibition of diacylglycerol kinase by R59022 activate protein kinase C and (ii) 2-bromooctanoate increases diacylglycerols but also has other effects on hepatocyte metabolism.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002210:Caprylates / Q000494:pharmacology*; D004075:Diglycerides / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D006005:Phosphorylases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011744:Pyrimidinones / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014667:Vasopressins / Q000494:pharmacology
D002210:Caprylates; D004075:Diglycerides; D005989:Glycerides; D011744:Pyrimidinones; D013844:Thiazoles; D014667:Vasopressins; C019279:2-bromooctanoic acid; D005934:Glucagon; C047505:R 59022; D006005:Phosphorylases; D006006:Glycogen Synthase; D011493:Protein Kinase C; D002118:Calcium; D004837:Epinephrine