Novel mechanism of heterologous desensitization of adenylate cyclase: prostaglandins bind with different affinities to both stimulatory and inhibitory receptors on platelets.
Prostaglandins E1, I2, and D2 (PGE1, PGI2, and PGD2) all stimulate and desensitize platelet adenylate cyclase, giving rise to peak and plateau effects in the time course of cyclic AMP metabolism in the intact cell. The peak and plateau effects vary with prostaglandin concentration to a different extent for each prostaglandin. However, at high concentrations, all prostaglandins give rise to the same time course of cyclic AMP formation. Differences in the extent of activation and desensitization can be modeled in terms of distinct stimulatory and slow-acting inhibitory receptors that differ in affinity for each prostaglandin but lead to the same maximum extent of activation and desensitization for all prostaglandins. The affinity for the stimulatory receptor is in the order PGI2 greater than PGE1 much greater than PGD2; the affinity for the inhibitory receptor is in the order of PGE1 greater than PGI2 much greater than PGD2. In addition, the inhibitory receptor binds PGE1 more tightly than the stimulatory receptor, whereas in the case of PGI2 or PGD2, the stimulatory receptor binds agonist more tightly than the inhibitory receptor. It is shown that the model gives rise to heterologous desensitization such that PGE1 readily inhibits PGI2- and PGD2-stimulated cyclic AMP formation, because it has high affinity for the inhibitory receptor. At the same time, because the final steady state concentration of cyclic AMP depends on the fractional occupancy of both the stimulatory and inhibitory receptors, PGE1 can cause either a rise or fall in cyclic AMP level, depending on the concentration of PGI2 or PGD2 used to challenge the platelets before PGE1 addition. The presence of a distinct inhibitory receptor may represent a general mechanism of autocoid desensitization, buffering cellular response against transient localized increases in agonist concentration that may occur when agonists are produced close to their sites of action.
Department of Pharmacology, Temple University Health Sciences Center, Philadelphia, Pennsylvania 19140.
B
B
Ashby
D000262:Adenylyl Cyclases / Q000032:analysis*; D000527:Alprostadil / Q000378:metabolism / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D011464:Epoprostenol / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D016285:Iloprost; D015230:Prostaglandin D2 / Q000378:metabolism / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000378:metabolism
D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D011464:Epoprostenol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000527:Alprostadil; D016285:Iloprost; D015230:Prostaglandin D2