Somatostatin Receptor Subtypes 2 and 5 Inhibit Corticotropin-Releasing Hormone-Stimulated Adrenocorticotropin Secretion from AtT-20 Cells

Abstract

Somatostatin (SRIH) regulates pituitary adrenocorticotropin (ACTH) secretion by interacting with a family of homologous G protein-coupled membrane receptors. The SRIH receptor subtypes (sst₁–sst₅) 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 ¹²⁵I-SRIH-14 and ¹²⁵I-SRIH-28 showed that SRIH-14 and SRIH-28 recognized specific, high-affinity and saturable membrane-binding sites. Nonpeptidyl agonists with selectivity for the sst₂ (L-779,976; compound 2) or sst₁/sst₅) (L-817,818; compound 5) receptor subtypes potently displaced ¹²⁵I-SRIH-28 from AtT-20 cell membranes, while agonists selective for the sst₁ (L-779,591; compound 1), sst₃ (L-796,778; compound 3) or sst₄ (L-803,087; compound 4) subtypes were inactive. Tyr¹¹-SRIH-14, compound 2 (sst₂) or compound 5 (sst₅) inhibited forskolin and corticotropin-releasing hormone (CRH)-induced increases in intracellular cAMP. Furthermore, the sst₂ and sst₅ agonists potently inhibited CRH-induced ACTH release from AtT-20 cells. These results provide the first evidence that sst₂ and sst₅ receptor subtypes, but not sst₁, sst₃ or sst₄, inhibit cAMP accumulation and regulate ACTH secretion in the AtT-20 cell model of the rodent corticotrope.

Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function

“…To evaluate ACTH secretory response to CRH in vitro, AtT20/D16v-F2 cells were incubated for 0, 2, 5, 10, 15, and 30 min with CRH at 100 nM, a concentration at which CRH is known to induce ACTH secretion in these cells (Strowski et al 2002). ACTH was then assayed in the condition medium.…”

Regulation of CRH-induced secretion of ACTH and corticosterone by SOM230 in rats

“…Among them are the sst2-prefering agonist octreotide, and the multireceptor ligand SOM230 which binds to sst1, sst2, sst3 and sst5 with high affinity, having a 30, 5 and 40 fold higher affinity to sst1, sst3 and sst5 receptors, respectively, compared with octreotide (4). It has been reported that sst2-and sst5-specific agonists inhibit CRH-induced ACTH release from AtT-20 cells (5). Although individual clinical case reports indicate that octreotide was able to restore eucortisolemia in patients presenting with an ACTH-dependent Cushing's syndrome (6), the efficacy of the sst2-prefering agonist, octreotide, could not be established in clinical trials (7).…”

Somatostatin and somatostatin receptors in Cushing's disease

“…IC 50 values of inhibition suggested a sst 5 -like response of ACTHinhibition. Both sst 2 and sst 5 are involved in the inhibition of ACTH release and cAMP production in AtT20 cells [56] and a functional superiority of sst 5 over sst 2 has been suggested by others as well [57,58]. On the other hand, sst 2 receptors, albeit at low level, are co-expressed with sst 5 receptors in corticotroph adenomas as well.…”