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Desensitization of beta adrenergic receptors linked to adrenocorticotropin secretion
Abstract:
Stimulation of beta adrenergic receptors on AtT-20 cells increases intracellular cyclic AMP levels and adrenocorticotropin hormone (ACTH) release. Pretreatment of these cells with catecholamines reduces the ability of (-)-isoproterenol to stimulate both cyclic AMP formation and ACTH secretion. This beta receptor desensitization is time- and dose-dependent and is reversible. Various beta adrenergic agonists can induce this desensitization with a rank order of potency of salmefamol greater than or equal to (-)-isoproterenol greater than or equal to epinephrine greater than or equal to norepinephrine greater than or equal to (+)-isoproterenol. (+/-)-Propranolol but not practolol can block the (-)-isoproterenol-induced beta receptor desensitization. Long-term treatment of AtT-20 cells with (-)-isoproterenol reduces the density of beta receptors but does not affect the affinity of these sites for [3H]dihydroalprenolol. In addition to desensitizing beta receptors, (-)-isoproterenol pretreatment enhances basal ACTH secretion. This effect was dose-dependent and blocked by (+/-)-propranolol. Forskolin-stimulated cyclic AMP formation and ACTH secretion was not altered by (-)-isoproterenol treatment indicating that the desensitization of beta receptors on AtT-20 cells is the result of receptor-adenylate cyclase uncoupling. No cross-desensitization of corticotropin releasing factor or vasoactive intestinal peptide receptors occurred as (-)-isoproterenol treatment did not alter the effect of these peptides on cyclic AMP synthesis or ACTH secretion.
Insights
Beta adrenergic receptor desensitization in AtT-20 cells reduces cyclic AMP and adrenocorticotropin hormone (ACTH) release. This desensitization is reversible and involves receptor-adenylate cyclase uncoupling, not affecting other peptide receptors.
Area of Science:
- Pharmacology
- Cell Biology
- Endocrinology
Background:
- Beta adrenergic receptors on AtT-20 cells mediate cyclic AMP production and adrenocorticotropin hormone (ACTH) release.
- Catecholamine pretreatment desensitizes these beta receptors, reducing their responsiveness.
Purpose of the Study:
- To investigate the characteristics and mechanisms of beta adrenergic receptor desensitization in AtT-20 cells.
- To determine the effects of desensitization on ACTH secretion and receptor-adenylate cyclase coupling.
Main Methods:
- Treatment of AtT-20 cells with various beta adrenergic agonists and antagonists.
- Measurement of intracellular cyclic AMP levels and ACTH release.
- Assessment of beta receptor density and affinity using radioligand binding.
Main Results:
- Beta adrenergic agonists induced dose- and time-dependent desensitization, with salmefamol and isoproterenol being potent.
- Desensitization reduced cyclic AMP and ACTH responses, was reversible, and involved receptor-adenylate cyclase uncoupling.
- (-)-Isoproterenol treatment decreased beta receptor density without altering affinity and enhanced basal ACTH secretion.
Conclusions:
- Beta adrenergic receptor desensitization in AtT-20 cells is a specific phenomenon mediated by receptor-adenylate cyclase uncoupling.
- This desensitization does not affect responses mediated by corticotropin-releasing factor or vasoactive intestinal peptide receptors.
- The findings provide insights into the regulation of ACTH secretion and beta-adrenergic signaling pathways.