Interrelationships between PGE1 and PGI2 binding and stimulation of adenylate cyclase.
The effects of prostaglandin E1 (PGE1) and prostacyclin (PGI2) on hepatic adenylate cyclase were studied in plasma membranes isolated from Sprague-Dawley rat livers. Both PGE1 and PGI2 stimulated this enzyme complex to the same maximal levels and with approximately the same EC50 (10(-7) M). Maximally stimulating concentrations of PGE1 and PGI2 were examined alone and together; their effects were not additive, indicating that the same enzyme complex was shared. Although a receptor for PGE1 could be demonstrated with a dissociation constant of 1 X 10(-8) M, PGI2 was only 1/100 as effective in competing for PGE1 binding sites (KD, 1 X 10(-6) M), indicating that these two prostaglandins may act via separate membrane receptors. PGI2 is known to be unstable at neutral pH; however, we have determined its half-life during these assays by a sensitive bioassay and concluded that the degradation of PGI2 is not sufficient to account for its inability to dissociate [3H]PGE1 binding. Further evidence that PGI2 might act through a distinct receptor was found in animals whose PGE1 receptors were 40% downregulated with a corresponding 28% decrease in PGE1-sensitive adenylate cyclase activity. These membranes had no such decrease in PGI2-sensitive adenylate cyclase activity. We conclude that 1) hepatic adenylate cyclase is equally sensitive to PGE1 and PGI2; 2) the same adenylate cyclase complex responds to both prostaglandins; and 3) PGE1 and PGI2 interact with separate membrane receptors in rat liver.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000527:Alprostadil; D000818:Animals; D002460:Cell Line / Q000378:metabolism; D015232:Dinoprostone; D004789:Enzyme Activation; D011464:Epoprostenol / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D011453:Prostaglandins / Q000378:metabolism*; D011458:Prostaglandins E / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D018078:Receptors, Prostaglandin E
D011453:Prostaglandins; D011458:Prostaglandins E; D011956:Receptors, Cell Surface; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D011464:Epoprostenol; D000262:Adenylyl Cyclases; D000527:Alprostadil; D015232:Dinoprostone