Muscarinic cholinergic receptors in mouse pituitary tumor cells: prolonged agonist pretreatment decreases receptor content and increases forskolin- and hormone-stimulated cyclic AMP synthesis and adrenocorticotropin secretion
Heisler, S.; Desjardins, D.; Nguyen, M.H.
Journal of Pharmacology and Experimental Therapeutics 232(1): 232-238
1985
ISSN/ISBN: 0022-3565 PMID: 2981317 Document Number: 246084
Muscarinic receptor activation on the AtT-20 clonal line of mouse pituitary corticotrophs, inhibits forskolin-stimulated cyclic AMP formation and adrenocorticotropin secretion. In this study, the effect of prolonged receptor stimulation with the muscarinic agonist oxotremorine was found to reduce, in a time-dependent manner, the ability of oxotremorine to inhibit the AtT-20 cell response to forskolin. Pretreatment with oxotremorine also reduced the density of muscarinic receptors without affecting the affinity of these sites for [3H]quinuclidinyl benzilate. In addition to desensitizing the muscarinic receptor, oxotremorine pretreatment also enhanced the ability of forskolin to stimulate cyclic AMP formation and adrenocorticotropin secretion. The apparent sensitizing effect on cyclic AMP synthesis, extended to other muscarinic agents as well as other secretory agonists, was dependent on the oxotremorine concentration used during pretreatment and required at least 2 hr of pretreatment. Enhancement of forskolin-stimulated cyclic AMP accumulation by oxotremorine pretreatment was blocked by cycloheximide and reversed by the muscarinic antagonist, (-)-scopolamine, or by a 5-hr recovery period after pretreatment. The data suggest that prolonged muscarinic receptor activation (rather than simple occupancy) leads to an enhancement of adenylate cyclase activity in AtT-20 cells; whether this effect is coupled to the progressive loss of the inhibitory function of the muscarinic receptor and the receptor down-regulation is unknown.