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Titolo:
Cloning, expression and pharmacological characterisation of the mouse somatostatin sst(5) receptor
Autore:
Feuerbach, D; Fehlmann, D; Nunn, C; Siehler, S; Langenegger, D; Bouhelal, R; Seuwen, K; Hoyer, D;
Indirizzi:
Novartis Pharma AG, Nervous Syst Res, CH-4002 Basel, Switzerland Novartis Pharma AG Basel Switzerland CH-4002 CH-4002 Basel, Switzerland
Titolo Testata:
NEUROPHARMACOLOGY
fascicolo: 8, volume: 39, anno: 2000,
pagine: 1451 - 1462
SICI:
0028-3908(2000)39:8<1451:CEAPCO>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
MOLECULAR-CLONING; PREFERENTIAL AFFINITY; RAT-BRAIN; SUBTYPES; PITUITARY; BINDING; TYPE-5; LABELS; GENE;
Keywords:
somatostatin (SRIF); mouse somatostatin receptor 5 (msst(5)); CCL39 Chinese hamster lung fibroblast cells; serum responsive element (SRE); luciferase; in situ hybridisation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Hoyer, D Novartis Pharma AG, Nervous Syst Res, S-386-745, CH-4002 Basel, Switzerland Novartis Pharma AG S-386-745 Basel Switzerland CH-4002 itzerland
Citazione:
D. Feuerbach et al., "Cloning, expression and pharmacological characterisation of the mouse somatostatin sst(5) receptor", NEUROPHARM, 39(8), 2000, pp. 1451-1462

Abstract

The mouse somatostatin (somatotropin release inhibiting factor, SRIF) sat,receptor coding sequence was cloned from a mouse BALB/c genomic library. It shows 97% and 81% homology with the corresponding rat and human receptors, respectively. The msst(5) receptor messenger RNA (mRNA) is present at lowlevels in the adult mouse brain, with significant expression in a few nuclei only, e.g. in the septum (lateral septal nuclei) or the amygdala (medialamygdaloid nucleus); very few signals were observed in the mesencephalon, metencephalon, and myelencephalon (except the dorsal motor nucleus of the vagus nerve). The msst(5) receptor was stably expressed in the hamster fibroblast cell line CCL39-SRE-Luci, which harbours the luciferase reporter genedriven by the serum responsive element. [I-125]LTT-SRIF-28 ([Leu(8), D-Trp(22), I-125-Tyr(25)]-SRIF-28), [I-125]Tyr(10)-CST, [I-125]CGP 23996, and [I-125]Tyr(3)-octreotide labelled msst(5) receptors with high affinity (pK(d)values: 11.0, 10.15, 9.75 and 9.43) and in a saturable manner, but defineddifferent Bmax values: 697, 495, 540 and 144 fmoles/mg, respectively. [I-125]LTT-SRIF-28-labelled sites displayed the following rank order: SRIF28> rCST-14> somatuline > CCP-23996= SRIF-14= octreotide, whereas [I-125]Tyr(3)-octreotide-labelled sites displayed a different profile: octreotide > SRIF-28> rCST-14= somatuline > SRIF-14> CGP-23996. The pharmacological profiles determined with [I-125]LTT-SRIF-28, [I-125]CGP 23996 and [I-125]Tyr(10)-CSTcorrelated highly significantly (r(2) =0.88-0.99), whereas [I-125]Tyr(3)-octreotide binding was rather divergent (r(2) =0.77). Also, human and mouse sst(5) receptor profiles are very different, e.g. r(2) =0.385 for [I-125]Tyr(10)-CST and r(2) =0.323 for [I-125]LTT-SRIF-28-labelled sites. Somatostatin induces expression of luciferase reporter gene in CCL39-SRE-Luci cells. The profile was consistent with a msst(5) receptor-mediated effect althoughapparent potency in the luciferase assay was much reduced compared to radioligand binding data. Octreotide = SRIE28> rCST-14= SRIF-14= CGP-23996. Octreotide, SRIF-28, BIM23052 and D Tyr Cyanamid 154806 behaved as full or nearly full agonists in comparison to SRIF-14, whereas the other compounds hadrelative efficacies of 40 to 70%. The present study shows that agonists radioligands define apparently different receptor populations in terms of number of sites and pharmacological profile in cells expressing a single recombinant receptor. These variations suggest that the conformation of the ligand receptor complex may vary depending on the agonist. Further, the msst(5)receptor, although primarily coupled to Gi/Go proteins, is able to stimulate luciferase gene expression driven by the serum responsive element. Finally, it is suggested that putative sst(2) selective agonists e.g. octreotide, RC160 or BIM23027 show similar or higher potency at msst(5) receptors than SRIF-14. (C) 2000 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/12/20 alle ore 13:14:51