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1Department of Internal Medicine, Section Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands; 2Novartis Institutes for Biomedical Research, Oncology Research, and Neuroscience Research, Novartis Pharma AG, Basel, Switzerland; 3Dipartimento di Fisiologica e Biochimica "G. Moruzzi", Università di Pisa, Italy; and 4Endocrinology Research Group, IPSEN Pharmaceuticals, Milford, Massachusetts
Submitted 5 January 2005 ; accepted in final form 8 March 2005
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 sst2A+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 (Bmax) by 72% when 125I-Tyr3-labeled OCT was used as radioligand, whereas Bmax 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.
Cushing’s disease; adrenocorticotropic hormone; glucocorticoid
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