Somatostatin receptor subtypes 2 and 5 inhibit corticotropin-releasing hormone-stimulated adrenocorticotropin secretion from AtT-20 cells.
Somatostatin (SRIH) regulates pituitary adrenocorticotropin (ACTH) secretion by interacting with a family of homologous G protein-coupled membrane receptors. The SRIH receptor subtypes (sst(1)-sst(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 (125)I-SRIH-14 and (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(2) (L-779,976; compound 2) or sst(1)/sst(5)) (L-817,818; compound 5) receptor subtypes potently displaced (125)I-SRIH-28 from AtT-20 cell membranes, while agonists selective for the sst(1) (L-779,591; compound 1), sst(3) (L-796,778; compound 3) or sst(4) (L-803,087; compound 4) subtypes were inactive. Tyr(11)-SRIH-14, compound 2 (sst(2)) or compound 5 (sst(5)) inhibited forskolin and corticotropin-releasing hormone (CRH)-induced increases in intracellular cAMP. Furthermore, the sst(2) and sst(5) agonists potently inhibited CRH-induced ACTH release from AtT-20 cells. These results provide the first evidence that sst(2) and sst(5) receptor subtypes, but not sst(1), sst(3) or sst(4), inhibit cAMP accumulation and regulate ACTH secretion in the AtT-20 cell model of the rodent corticotrope.
Strowski
Mathias Z
MZ
Merck Research Laboratories, Rahway, NJ, USA.
Dashkevicz
Michael P
MP
Parmar
Rupa M
RM
Wilkinson
Hilary
H
Kohler
Martin
M
Schaeffer
James M
JM
Blake
Allan D
AD
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D001667:Binding, Competitive; D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism / Q000502:physiology*; D020690:GTPase-Activating Proteins; D007457:Iodine Radioisotopes; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D013004:Somatostatin / Q000378:metabolism; D053561:Somatostatin-28; D020710:RGS Proteins
D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D005656:Fungal Proteins; D020690:GTPase-Activating Proteins; D007457:Iodine Radioisotopes; D017481:Receptors, Somatostatin; D029701:Saccharomyces cerevisiae Proteins; D013004:Somatostatin; D053561:Somatostatin-28; C094301:SST2 protein, S cerevisiae; D020710:RGS Proteins; C094573:somatostatin receptor 5