Somatostatin-14 and somatostatin-28 pretreatment down-regulate somatostatin-14 receptors and have biphasic effects on forskolin-stimulated cyclic adenosine, 3',5'-monophosphate synthesis and adrenocorticotropin secretion in mouse anterior pituitary tumor cells.
Activation of somatostatin-14 (S-14) receptors on mouse AtT-20 pituitary tumor cells by S-14 or somatostatin-28 (S-28) inhibits forskolin-stimulated cAMP synthesis and ACTH secretion. In this study, the effects of prolonged exposure of cells to S-14 or S-28 was found to reduce, in a time- and concentration-dependent fashion, the density of S-14 receptors without affecting the affinity of these sites for [125I]Tyr11-S-14. This response was rapidly reversible after removal of peptide from incubation media. Additionally, S-14 and S-28 pretreatment also resulted in a time-dependent sensitizing effect on forskolin-stimulated cAMP formation and ACTH secretion which preceded S-14 receptor down-regulation. Enhancement of the forskolin response was concentration dependent, with maximal effects observed at 10(-8) M with either peptide. Higher pretreatment concentrations of S-14 resulted in an abolition of the enhanced biological response to forskolin; pretreatment with S-28 (10(-6) M) depressed forskolin- and (-)isoproterenol-induced cAMP formation below levels observed in nonpretreated cells. The enhancing effect of S-14 and S-28 required new protein synthesis, since it was partially blocked by cycloheximide; the depressor effect was independent of new protein synthesis. Both the enhanced and depressed forskolin responses after peptide pretreatment were reversible after withdrawal of S-14 or S-28; normalization of the forskolin response (cAMP formation and ACTH secretion) followed the return to control levels of S-14 receptor density. Pretreatment of cells with 10(-8) M or 10(-6) M S-28 increased and decreased, respectively, the ACTH secretory response to agonists which act in the absence of prior cAMP synthesis such as 8-bromo-cAMP, A-23187, and phorbol ester. The data suggest that S-14 receptor down-regulation is not causally associated with the sensitizing effects of S-14 and S-28 on adenylate cyclase and that the S-14 receptor may be also coupled to other effector systems which are involved in regulating the secretory function of AtT-20 cells.
Heisler
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Srikant
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D000262:Adenylyl Cyclases / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005576:Colforsin; D000242:Cyclic AMP / Q000096:biosynthesis; D004224:Diterpenes / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D017481:Receptors, Somatostatin; D013004:Somatostatin / Q000378:metabolism / Q000494:pharmacology*; D053561:Somatostatin-28
D004224:Diterpenes; D011956:Receptors, Cell Surface; D017481:Receptors, Somatostatin; D005576:Colforsin; D013004:Somatostatin; D053561:Somatostatin-28; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol