title: Agonist- and mitogen-induced desensitization of isoproterenol-stimulated cyclic AMP formation in mouse epidermis in vivo.
abstract: Injection of the beta-adrenergic agonist isoproterenol causes a rapid desensitization of cyclic AMP formation to subsequent beta-adrenergic challenge in mouse epidermis. Long-lasting catecholamine refractoriness is also observed after prolonged treatment of mouse skin with certain mitogens such as the phorbol ester TPA (tumor promoter), 12-retinoylphorbol-acetate, the TPA-analogue C14:4phorbol acetate or the divalent cation ionophore A 23187 but not after mitogenic stimulation by phorbol-12,13-dibenzoate and 4-O-methyl-TPA or by means of chemical depilation, removal of the horny layer or skin massage. Thus no clear-cut correlation exists between the desensitizing efficacy of a given treatment and its ability to provoke epidermal hyperplasia and to promote skin tumor formation. Both, agonist- and mitogen-induced desensitization are dependent on protein synthesis in epidermis, the mitogen-induced effect is in addition dependent on RNA synthesis. The putative desensitizing protein is not cyclic AMP phosphodiesterase but could be a feedback inhibitor of receptor-cyclase interaction ("refractoriness protein") which has recently been proposed to be responsible for catecholamine tachyphylaxis in certain in vitro systems. In contrast to epidermal hyperproliferation mitogen-induced tachyphylaxis is not mediated by prostaglandin synthesis and is apparently also independent of initial cyclic AMP formation. It can be prevented, however, by the antimitotic synthetic corticoid fluocinolone acetonide but not by colchicine, vincristine cytochalasin B or adrenergic blockers.
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology*; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology*; D010704:Phorbols / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D008934:Mitogens; D010703:Phorbol Esters; D010704:Phorbols; D000001:Calcimycin; C032975:12-O-tetradeca-2,4,6,8-tetranoylphorbol-13-acetate; C032974:12-O-retinoylphorbol-13-acetate; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate