The role of protein kinase C in histamine secretion from mast cells.
Receptor activation on the cell surface is coupled through a guanine nucleotide regulatory protein to polyphosphoinositide phosphodiesterase. The activation of this enzyme catalyses the hydrolysis of phosphatidylinositol biphosphate. One of the products of this hydrolysis is diacylglycerol, which activates protein kinase C. It can also be activated by tumour-promoting phorbol esters. The synthetic diacylglycerol, 1-oleoyl-2-acetyl-rac-glycerol (OAG) and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) have been used to stimulate protein kinase C in a pure population of rat peritoneal mast cells. Both of them caused histamine release, but the rate of release with TPA or OAG alone was slow. The release was inhibited by blocking the oxidative energy metabolism with antimycin A, and was associated with progressive exocytosis, showing that it is a secretory process. Studies on the interaction between the stimulation of protein kinase C by OAG/TPA and the secretagogues showed a dual effect, both potentiation and inhibition. Antigen (in sensitized cells) and compound 48/80 showed this pattern of response. With the calcium ionophore, A23187, potentiation was the dominant effect, although some inhibition could be shown with TPA. This is possibly related to the large calcium influx which causes translocation of protein kinase C to the membranes and enhances its activity. The potentiation suggests that protein kinase C is involved in the secretion process by the secretagogues, while the inhibition reflects a regulatory function, which is apparently exerted through an inhibition of phosphatidylinositol breakdown. Calcium uptake was enhanced by both TPA and OAG. Protein kinase C may thus contribute to the replenishment of the intracellular calcium stores after the secretory response.
Chakravarty
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Department of Pharmacology, Odense University, Denmark.
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D006636:Histamine Release; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D011493:Protein Kinase C / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004075:Diglycerides; D000001:Calcimycin; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium