PHORBOL ESTER HAS DIFFERENT EFFECTS ON FORSKOLIN AND BETA-ADRENERGIC-STIMULATED CAMP ACCUMULATION IN MOUSE PAROTID ACINI

Phorbol 12-myristate 13-acetate (TPA) augmented the effects of forskol in, and inhibited the effects of isoproterenol on cAMP accumulation in mouse parotid acini. Treatment of intact cells with the phosphodieste rase inhibitor, 3-isobutyl-1-methylxanthine (MIX), blocked TPA inhibit ion of isoproterenol but not forskolin-stimulated cAMP accumulation. T PA also caused the translocation of protein kinase C (PKC) from cytoso l to membrane. Pre-treatment of parotid acini with TPA for 30 min enha nced the forskolin and isoproterenol-stimulated adenylate cyclase acti vity in isolated parotid membranes. Addition of purified PKC (pPKC) to parotid membranes mimicked the effects of TPA in increasing cAMP synt hesis; the effects were blocked in the absence of calcium and phosphol ipid, and in the presence of the synthetic peptide (PKC 19-36). Purifi ed PKC also mimicked the effects of TPA in augmenting forskolin and is oproterenol-stimulated adenylate cyclase activities in the cell-free s ystem. Data suggest that the differential regulation of forskolin and isoproterenol-stimulated cAMP accumulation by TPA results from modific ation of enzymes that synthesize and degrade cAMP.