Evidence for a second desensitized state of beta-adrenergic receptor with low affinity for beta-antagonists and normal reactivity towards beta-agonists in adipocyte membranes previously exposed to beta-antagonists.
When adipocyte membranes are successively exposed to (-)-propranolol or (+/- alprenolol at 25 or 4 degrees C, repeatedly washed and then assayed for (-)-[3H]dihydroalprenolol binding, the apparent number of beta-adrenergic binding sites is markedly decreased. Induction of this peculiar type of receptor desensitization does not require prolonged exposure of the membranes to the beta-adrenergic antagonists (half-time: 1 min), is stereospecific, concentration-dependent and almost complete with high concentrations of antagonists. p[NH]ppG, which reduces the affinity of fat cell beta-adrenergic receptors for agonists, does not prevent the antagonist-induced decrease in the receptor number. The magnitude of the desensitizating effect induced separately by (-)-isoproterenol and (-)-propranolol is not additive in membranes exposed to both drugs, suggesting that the receptors lost after exposure to agonists are the same sites as part of those lost after exposure to antagonists. However, contrary to the results found in membranes desensitized by agonists, adenylate cyclase activity remained fully responsive to catecholamines in membranes exposed to beta-antagonists. As shown by kinetic studies on (-)-[3H]dihydroalprenolol binding, this beta-antagonist-induced receptor desensitization is reversible after prolonged incubation. These data which have never yet been described in the other reported desensitizable beta-adrenergic systems, suggest that, when exposed to beta-antagonists, the fat cell beta-adrenergic receptors undergo a conformational change leading to a peculiar state which has low affinity for antagonists but behaves towards agonists as does the receptor in its resting state.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D004082:Dihydroalprenolol / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate; D007545:Isoproterenol / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D051381:Rats; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D002395:Catecholamines; D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; D006165:Guanylyl Imidodiphosphate; D004082:Dihydroalprenolol; D011433:Propranolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol