Desensitization of adenylate cyclase responses following exposure to IP prostanoid receptor agonists. Homologous and heterologous desensitization exhibit the same time course.
Pretreatment of NG108-15 cells with 0.03-25 microM prostaglandin E1 (PGE1) produced decreases in the maximal stimulation of adenylate cyclase activity produced by iloprost, N-ethylcarboxamidoadenosine and sodium fluoride. The rate of desensitization to all three agents was dependent on the concentration of PGE1 used, but at each concentration of PGE1 the rate of loss of responsiveness to each agent was the same, suggesting that the decreases in responsiveness may be mediated by a single process. Functional desensitization was accompanied by a decrease in the specific binding of [3H]iloprost, consistent with a 75-80% decrease in IP receptor number, with no change in the coupling of the remaining IP receptors to G protein. At each concentration of PGE1 used, the times taken for half maximal decreases in receptor number and functional responsiveness were similar, suggesting that IP receptor down-regulation is a relatively early event in desensitization. IP receptor down-regulation could be inhibited partially by 100 microM chloroquine, suggesting that lysosomal breakdown of receptors may be occurring.
Krane
A
A
Department of Pharmacology, Medical School, University of Birmingham, U.K.
MacDermot
J
J
Keen
M
M
D000262:Adenylyl Cyclases / Q000187:drug effects*; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D015536:Down-Regulation; D016285:Iloprost / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D051381:Rats; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D000262:Adenylyl Cyclases; D000527:Alprostadil; D016285:Iloprost