| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Internal Medicine, section Endocrinology, Erasmus MC, Rotterdam, The Netherlands
2 Novartis Pharma AG, Novartis Institutes for Biomedical Research, Oncology Research and Neuroscience Research, Basel, Switzerland
3 Dipartimento di Fisiologica e Biochimica G. Moruzzi, Universita di Pisa, Pisa, Italy
4 Endocrinology Research Group, IPSEN, Milford, Massachusetts, USA
* To whom correspondence should be addressed. E-mail: j.vanderhoek{at}erasmusmc.nl.
In a series of human corticotroph adenomas, we recently found predominant mRNA-expression of somatostatin (SS) receptor subtype (sst) 5. After 72h, 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 GTP
S binding in AtT-20 cell membranes as compared with OCT. SOM230 potently suppressed CRH-induced ACTH release, which was not affected by 48h dexamethasone (DEX) pre-treatment. However, DEX attenuated the inhibitory effects of OCT on ACTH release, whereas it increased the inhibitory potency of BIM-23268, a sst5-specific analog, on ACTH release. Quantitative-PCR analysis showed that DEX lowered sst2A+2B mRNA expression significantly after 24 and 48h, 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]-Octreotide 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 pre-incubation, compared with OCT, both SOM230 and BIM-23268 showed a significant 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 disease.
This article has been cited by other articles:
|
|
 |
|
  C de Bruin, R A Feelders, A M Waaijers, P M van Koetsveld, D M Sprij-Mooij, S W J Lamberts, and L J Hofland Differential regulation of human dopamine D2 and somatostatin receptor subtype expression by glucocorticoids in vitro J. Mol. Endocrinol., January 1, 2009; 42(1): 47 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Giordano, A Picu, L Bonelli, F Broglio, F Prodam, S Grottoli, G Muccioli, E Ghigo, and E Arvat The activation of somatostatinergic receptors by either somatostatin-14 or cortistatin-17 often inhibits ACTH hypersecretion in patients with Cushing's disease Eur. J. Endocrinol., October 1, 2007; 157(4): 393 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. van der Hoek, S. W J Lamberts, and L. J Hofland Preclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomas Eur. J. Endocrinol., April 1, 2007; 156(suppl_1): S45 - S51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Armani, E. Catalani, A. Balbarini, P. Bagnoli, and D. Cervia Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages J. Leukoc. Biol., March 1, 2007; 81(3): 845 - 855. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
