Role of protein kinase C in the regulation of histamine and bradykinin stimulated inositol polyphosphate turnover in adrenal chromaffin cells.

1. The possibility that bradykinin- or histamine-stimulated inositol polyphosphate accumulation may be regulated by protein kinase C (PKC) in bovine adrenal chromaffin cells has been addressed. 2. Initial experiments confirmed that the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) dramatically inhibited agonist-stimulated [3H]-inositol phosphate accumulations in [3H]-inositol prelabelled cells. In contrast, the PKC inhibitor, Ro 31-8220, did not affect this response. 3. Histamine (100 microM) or bradykinin (100 nM) evoked rapid increases in inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) mass accumulations (maximal accumulations within 10 s and 30 s, respectively) which declined towards basal values over a 10 min incubation period. TPA (1 microM) significantly attenuated the peak Ins(1,4,5)P3 response to bradykinin and histamine by 30% and 70% respectively. In contrast, TPA did not significantly affect agonist-stimulated Ins(1,3,4,5)P4 responses. 4. Ro 31-8220 (10 microM) significantly enhanced the maximal Ins(1,4,5)P3 accumulations elicited by both bradykinin and histamine. 5. The results indicate that the initial Ins(1,4,5)P3 response to either bradykinin or histamine in bovine adrenal chromaffin cells can be attenuated by PKC activation by phorbol ester and enhanced by PKC inhibition by Ro 31-8220. In contrast, agonist-stimulated Ins(1,3,4,5)P4 accumulation does not appear to be affected by these manipulations of PKC activity. Possible bases for differential modulation of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 are discussed.