Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells

Abstract

In a series of human corticotroph adenomas, we recently found predominant mRNA expression of somatostatin (SS) receptor subtype 5 (sst5). After 72 h, the multiligand SS analog SOM230, which has a very high sst5 binding affinity, but not Octreotide (OCT), significantly inhibited basal ACTH release. To further explore the role of sst5 in the regulation of ACTH release, we conducted additional studies with mouse AtT-20 cells. SOM230 showed a 7-fold higher ligand binding affinity and a 19-fold higher potency in stimulating guanosine 5'-O-(3-thiotriphosphate) binding in AtT-20 cell membranes compared with OCT. SOM230 potently suppressed CRH-induced ACTH release, which was not affected by 48-h dexamethasone (DEX) pretreatment. However, DEX attenuated the inhibitory effects of OCT on ACTH release, whereas it increased the inhibitory potency of BIM-23268, an sst5-specific analog, on ACTH release. Quantitative PCR analysis showed that DEX lowered sst(2A+2B) mRNA expression significantly after 24 and 48 h, whereas sst5 mRNA levels were not significantly affected by DEX treatment. Moreover, Scatchard analyses showed that DEX suppressed maximum binding capacity (B(max)) by 72% when 125I-Tyr3-labeled OCT was used as radioligand, whereas B(max) declined only by 17% when AtT-20 cells were treated with [125I-Tyr11]SS-14. These data suggest that the sst5 protein, compared with sst2, is more resistant to glucocorticoids. Finally, after SS analog preincubation, compared with OCT both SOM230 and BIM-23268 showed a significantly higher inhibitory effect on CRH-induced ACTH release. In conclusion, our data support the concept that the sst5 receptor might be a target for new therapeutic agents to treat Cushing's disease.

Somatostatin receptors in human adrenal gland tumors--immunohistochemical study.

“…The mRNA for mainly SSTR 5 was found in a series of human corticotropic adenomas [21]. No presence of SSTR 5 in any of 10 studied pheochromocytomas was shown by this method and SSTR 1 was detected in almost all cases [18].…”

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

“…In vitro studies on human cells studying pituitary hormone secretion used 10 K8 M concentrations and showed inhibition of GH, thyrotrophin (TSH) and a-subunit release, with octreotide having a stronger effect than SOM230 (35)(36)(37). However, the maximal effective dose of SST analogues could be different for hormone release and anti-proliferative effects.…”

Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages

“…Because of their long-acting properties in vitro and in vivo, low molecular weight/metabolically stable analogs are more suitable for clinical application or experimental investigations than SRIF-14 [2,41]. Among synthetic ligands, we used the peptidyl multiligand analog SOM230, which binds with high affinity to sst 1,2,3,5 [42][43][44], and the peptidyl multiligand analog KE108, which binds with high affinity to all five SRIF receptors [44,45]. The sst 1 -selective peptidyl agonist CH-275 [35,41,46,47], the sst 2 -preferring peptiydyl agonist SMS 201-995 (also known as sandostatin or octreotide) [38,41,46,48,49], and the sst 2 -selective nonpeptidyl agonist L-779,976 [46, 49 -51] were also used in the absence or presence of the sst 1 -selective nonpeptydil antagonist SRA-880 [46,52,53] and the sst 2 -selective peptydil antagonist CYN [36,38,48,49,54].…”