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.