Studies have been carried out to better elucidate the regulatory properties of protein kinase C (PK-C). Results of investigations with rat pinealocytes indicate that an elevation of Ca2+ influx alone can initiate activation of PK-C. Treatments which elevate Ca2+ influx, including increased extracellular K+ and addition of the Ca2+ ionophore A23187, cause redistribution of PK-C to the membrane fraction. It was established that a close correlation exists between redistribution (activation) of PK-C by phenylephrine, K+, and A23187 and their ability to potentiate beta- adrenergic stimulation of cAMP and cGMP accumulation. Exposure of PK-C to )ow concentrations of H2O2 resulted in the rapid and parallel loss of phosphotransferase activity and phorbol ester tumor promoter binding. This oxidative inactivation of PK-C also occurred in intact cells exposed to a low concentration of H2O2, and suggests that such a free radical inactivation may be operative within cell populations to decrease PK-C activity. Treatment of P388 murine leukemic cells with the antineoplastic drug diaziquone (AZO) causes a rapid and pronounced inactivation of PK-C apparently through a mechanism involving the formation of free radicals. Protein kinase C activities have been determined in control (drug sensitive) and multidrugresistant human breast cancer KC cells, human KB carcinoma cells, and murine leukemic P388 cells. In all cases the drug-resistant cells expressed higher activities of both cytosolic and membrane pK-C compared to control, drug sensitive cells. These data suggest that an increase in a specific form of PK-C may play a roie in the development and modulation of multidrug resistance.
