title: Cyclic AMP-induced desensitization of G-protein-regulated phospholipase C in turkey erythrocyte membranes.
abstract: The interaction of the cyclic AMP and inositol lipid signalling systems was studied in turkey erythrocytes. Elevation of intracellular cyclic AMP concentrations by pretreatment of the cells with forskolin or 8-Br-cAMP resulted in a marked decrease in responsiveness of phospholipase C to G-protein activators in membranes prepared from treated cells. Decreases in responsiveness occurred with a t1/2 of approximately 5 min and were reversible after transfer of desensitized cells to drug-free medium. Pretreatment of the cells with forskolin inhibited inositol phosphate formation in a concentration-dependent manner and addition of the phosphodiesterase inhibitor IBMX 93-isobutyl-1-methylxanthine) during pretreatment increased the capacity of forskolin to desensitize phospholipase C activity. IBMX also produced a similar potentiation of forskolin-stimulated accumulation of cyclic AMP in turkey erythrocytes. Isoproterenol pretreatment of the cells induced, like forskolin, partial inhibition of inositol phosphate generation in response to G-protein activators and to P2y purinoceptor and beta-adrenoceptor agonists. The capacity of isoproterenol to induce desensitization of phospholipase C activity also was increased by the presence of IBMX during pretreatment of the cells. H8 (N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide), an inhibitor of cyclic AMP-regulated protein kinase, completely prevented forskolin-induced desensitization but only partially blocked isoproterenol-induced desensitization. These results indicate that the cyclic AMP signalling cascade has a major inhibitory influence on receptor- and G-protein-activated inositol lipid signaling.
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill 27599, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Galas
authors.forename: T K
authors.initials: TK
authors.lastname: Harden
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D019204:GTP-Binding Proteins / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013566:Sympathomimetics / Q000494:pharmacology; D014422:Turkeys; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D010726:Phosphodiesterase Inhibitors; D013566:Sympathomimetics; D005576:Colforsin; D000242:Cyclic AMP; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine