Heterologous desensitization of adenylate cyclase with prostaglandin E1 alters sensitivity to inhibitory as well as stimulatory agonists.
Adenylate cyclase in cultured human fibroblasts is activated by prostaglandin E1 (PGE1) or beta-adrenergic agonists, e.g., isoproterenol, and inhibited by muscarinic agonists. Incubation with PGE1 reduced adenylate cyclase responsiveness to both PGE1 and isoproterenol; this so-called heterologous desensitization is believed to result from impaired function of the stimulatory guanyl nucleotide-binding protein of the cyclase complex. The effect of heterologous desensitization by PGE1 on inhibition of adenylate cyclase by the muscarinic agonist oxotremorine was examined. Muscarinic inhibition of basal and isoproterenol-stimulated cAMP accumulation was attenuated following exposure to PGE1; the concentration of oxotremorine required for half-maximal inhibition of cAMP accumulation was increased. In both intact cells and membrane preparations the number of binding sites for [3H]scopolamine, a muscarinic antagonist, was unaltered by desensitization. Following exposure to PGE1, receptor affinity for oxotremorine, assessed by competition with [3H] scopolamine, and the guanyl nucleotide sensitivity of agonist binding were reduced. The amount of inhibitory guanyl nucleotide-binding regulatory protein available for [32P]ADP-ribosylation by pertussis toxin was unaltered by desensitization. Thus, heterologous desensitization of adenylate cyclase with the stimulatory agonist PGE1 alters sensitivity to inhibitory as well as stimulatory ligands.
Hsia
J A
JA
Hewlett
E L
EL
Moss
J
J
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000527:Alprostadil; D003080:Cold Temperature; D000242:Cyclic AMP / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D011458:Prostaglandins E / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000378:metabolism; D012601:Scopolamine / Q000378:metabolism; D013997:Time Factors
D011458:Prostaglandins E; D011976:Receptors, Muscarinic; D000246:Adenosine Diphosphate Ribose; D006165:Guanylyl Imidodiphosphate; D010095:Oxotremorine; D012601:Scopolamine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000527:Alprostadil; D007545:Isoproterenol