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|Title:||Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells||Authors:||Van der Hoek, Joost
Van Koetsveld, Peter M.
Feelders, Richard A.
Schmid, Herbert A.
Taylor, John E.
Culler, Michael D.
Lamberts, Steven W.J.
Hofland, Leo J.
|Keywords:||Cushing’s disease;Adrenocorticotropic hormone;Glucocorticoid||Issue Date:||2005||Publisher:||American Physiological Society||Source:||Van der Hoek, J. et al. 2005. Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. "American Journal of Physiology. Endocrinology and Metabolism" 289: E278–E287||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 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 CRHinduced
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.
L'articolo è disponibile sul sito dell'editore http://www.the-aps.org/index.htm
|Appears in Collections:||DISA - Archivio della produzione scientifica|
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