Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Pharmacological properties of the naturally occurring Phe-124-Cys variant of the human 5-HGT(1B) receptor: changes in ligand binding, G-protein coupling and second messenger formation
Autore:
Kiel, S; Bruss, M; Bonisch, H; Gothert, M;
Indirizzi:
Univ Bonn, Inst Pharmacol & Toxicol, D-53113 Bonn, Germany Univ Bonn Bonn Germany D-53113 harmacol & Toxicol, D-53113 Bonn, Germany
Titolo Testata:
PHARMACOGENETICS
fascicolo: 7, volume: 10, anno: 2000,
pagine: 655 - 666
SICI:
0960-314X(200010)10:7<655:PPOTNO>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN 5-HT1B RECEPTOR; GENETIC-VARIATION; C6-GLIAL CELLS; GUINEA-PIG; SEROTONIN; 5-HT1D-BETA; SUMATRIPTAN; ANTAGONIST; GR-127,935; SB-216641;
Keywords:
(Phe-124-Cys)h5-HT1B receptor; G protein coupling; [S-35]GTP gamma S binding; cAMP formation; pharmacogenetic differences;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Gothert, M Univ Bonn, Inst Pharmacol & Toxicol, Reuterstr 2B, D-53113 Bonn, Germany Univ Bonn Reuterstr 2B Bonn Germany D-53113 3113 Bonn, Germany
Citazione:
S. Kiel et al., "Pharmacological properties of the naturally occurring Phe-124-Cys variant of the human 5-HGT(1B) receptor: changes in ligand binding, G-protein coupling and second messenger formation", PHARMACOGEN, 10(7), 2000, pp. 655-666

Abstract

The aim of this study was to analyse whether substitution of phenylalaninein postion 124 of the human (h) 5-HT1B receptor by cysteine, a naturally occurring variant of this receptor, modifies not only ligand binding, but also G-protein coupling and second messenger formation. Stably transfected rat C6 glioma cells, which express either the h5-HT1B variant receptor (VR) or the wild-type receptor (WTR) were used. In saturation experiments with [H-3]5-carboxamidotryptamine ([H-3] 5-CT), the maximum binding (B-max) of theVR amounted to only 60% of that to WTR, In competition experiments with 1 nM [H-3]5-CT. the following 5-HT receptor ligands exhibited a higher affinity for the mutant receptor than for the WTR: L-694,247, 5-CT, 5-HT, sumatriptan (agonists listed at decreasing order of potency) and SB-224289 (a selective h5-HT1B receptor inverse agonist with competitive antagonistic properties). In contrast, the mixed 5-HT1B/1D receptor antagonist GR-127935 exhibited equal affinity for both isoforms. The efficacy of L-694,247, 5-CT, 5-HT and sumatriptan in stimulating [S-35]GTP gamma S binding (a measure of G protein coupling) to membranes of cells expressing the Vp. was approximately 50-65% lower compared to membranes of cells expressing the WTR, but theirpotency was 2.8-3.6-fold higher, SB-224289, which decreased [S-35]GTP gamma S binding when given alone, but not GR-127935, was more potent in antagonizing the stimulatory effect of 5-CT on [S-35]GTP gamma S binding to membranes expressing the VR compared to membranes expressing the WTR. In whole cells expressing the VR, 5-CT and sumatriptan inhibited the forskolin-stimulated cAMP accumulation 3.2-fold more potently than in cells expressing the WTR. In conclusion, our data suggest that the Phe-124-Cys mutation modifies the pharmacological properties of the h5-HT1B receptor and may account for pharmacogenetic differences in the action of h5-HT1B receptor ligands, Thus, the sumatriptan-induced vasospasm which occurs at low incidence as a side-effect in migraine therapy may be related to the expression of the (124-Cys)h5-HT1B receptor in patients with additional pathogenetic factors such ascoronary heart disease. Pharmacogenetics 10:655-666 (C) 2000 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/09/20 alle ore 07:59:42