| Abstrakt: |
Somatostatin (SRIH) regulates pituitary adrenocorticotropin (ACTH) secretion by interacting with a family of homologous G protein-coupled membrane receptors. The SRIH receptor subtypes (sst[sub 1] –sst[sub 5] ) that control ACTH release remain unknown. Using novel, subtype-selective SRIH analogs, we have identified the SRIH receptor subtypes involved in regulating ACTH release from AtT-20 cells, a model for cell line pituitary corticotropes. Radioligand-binding studies with [sup 125] I-SRIH-14 and [sup 125] I-SRIH-28 showed that SRIH-14 and SRIH-28 recognized specific, high-affinity and saturable membrane-binding sites. Nonpeptidyl agonists with selectivity for the sst[sub 2] (L-779,976; compound 2) or sst[sub 1] /sst[sub 5] ) (L-817,818; compound 5) receptor subtypes potently displaced [sup 125] I-SRIH-28 from AtT-20 cell membranes, while agonists selective for the sst[sub 1] (L-779,591; compound 1), sst[sub 3] (L-796,778; compound 3) or sst[sub 4] (L-803,087; compound 4) subtypes were inactive. Tyr[sup 11] -SRIH-14, compound 2 (sst[sub 2] ) or compound 5 (sst[sub 5] ) inhibited forskolin and corticotropin-releasing hormone (CRH)-induced increases in intracellular cAMP. Furthermore, the sst[sub 2] and sst[sub 5] agonists potently inhibited CRH-induced ACTH release from AtT-20 cells. These results provide the first evidence that sst[sub 2] and sst[sub 5] receptor subtypes, but not sst[sub 1] , sst[sub 3] or sst[sub 4] , inhibit cAMP accumulation and regulate ACTH secretion in the AtT-20 cell model of the rodent corticotrope.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR] |
