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This Article Full Text Full Text (PDF) All Versions of this Article: 289/2/E278    most recent 00004.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by van der Hoek, J. Articles by Hofland, L. J. Search for Related Content PubMed PubMed Citation Articles by van der Hoek, J. Articles by Hofland, L. J.

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

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 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.

Cushing’s disease; adrenocorticotropic hormone; glucocorticoid

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