Control of platelet protein kinase C activation by cyclic AMP.
Experiments were performed to elucidate the role of adenosine 3': 5'-cyclic monophosphate (cAMP) in the control of platelet protein kinase C (PKC) activation. Platelet aggregation and secretion in response to 4 beta-phorbol 12-myristate 13-acetate (PMA) or 1-oleoyl-2-acetylglycerol (OAG) were inhibited by dibutyryl cAMP in a dose-dependent manner. Inhibition of these functional activities paralleled a decrease in the PMA-induced phosphorylation of the Mr 47,000 substrate (p47) of PKC by pre-incubation of platelets with dibutyryl cAMP. These changes were also observed when platelet cAMP was increased by prostacyclin (PGI2), forskolin, or theophylline. The ADP scavenger creatine phosphate/creatine phosphokinase (CP/CPK) and the cyclooxygenase inhibitor indomethacin also diminished the aggregation and p47 phosphorylation responses to PMA or OAG. Pre-incubation of platelets with dibutyryl cAMP significantly potentiated the inhibition of aggregation and p47 phosphorylation effected by CP/CPK and indomethacin. These results are consistent with the model that PMA- or OAG-induced activation of platelets is amplified by secreted ADP and that the response to secreted ADP is inhibited by cAMP. Furthermore, the findings that increased intracellular cAMP inhibits PMA- or OAG-induced p47 phosphorylation in excess of that due solely to CP/CPK, and that cAMP significantly potentiates the effects of ADP removal and inhibition of cyclooxygenase in blocking p47 phosphorylation suggest that cAMP also exerts non-ADP-mediated inhibitory effects on PKC in intact platelets.
Kroll
M H
MH
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Zavoico
G B
GB
Schafer
A I
AI
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D001792:Blood Platelets / Q000201:enzymology*; D000242:Cyclic AMP / Q000494:pharmacology*; D004075:Diglycerides / Q000494:pharmacology; D011464:Epoprostenol / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010750:Phosphoproteins / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D011493:Protein Kinase C / Q000097:blood*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004075:Diglycerides; D010750:Phosphoproteins; D000244:Adenosine Diphosphate; D011464:Epoprostenol; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate