Mechanism of prostaglandin E2-induced glucose production in rat hepatocytes

Effects of prostaglandin E2 (PGE2) on glycogenolysis were examined in rat hepatocytes. In a batch incubation system using isolated hepatocytes, PGE2 increased glucose output dose-dependently. The glycogenolytic effect of PGE2 was detected at a concentration of 10(-11) M, and 10(-8) M PGE2 elicited the maximum glucose output, which was equal to that by glucagon. PGE2 did not increase cAMP at any dose tested (10(-11)-10(-4) M). Instead, PGE2 increased the cytoplasmic free calcium concentration ([Ca2+]c). When the effect of PGE2 on [Ca2+]c was studied in aequorin-loaded cells, the effect of PGE2 on [Ca2+]c was detected at 10(-12) M, and the magnitude of the response increased in a dose-dependent manner. PGE2 increased [Ca2+]c even in the presence of 1 microM extracellular calcium, suggesting that PGE2 mobilizes calcium from an intracellular pool. In line with these observations, PGE2 increased the production of inositol trisphosphate. Compared with the action of PGE2, 16,16-dimethyl-PGE2, a PGE2 analog, was less potent in stimulating glycogenolysis. These results indicate that PGE2 stimulates glycogenolysis by activating the calcium messenger system.