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Titolo:
Disparate ligand-mediated Ca2+ responses by wild-type, mutant Ser(200)Ala and Ser(204)Ala alpha(2A)-adrenoceptor: G(alpha 15) fusion proteins: evidence for multiple ligand-activation binding sites
Autore:
Pauwels, PJ; Colpaert, FC;
Indirizzi:
Ctr Rech Pierre Fabre, Dept Cellular & Mol Biol, F-81106 Castres, France Ctr Rech Pierre Fabre Castres France F-81106 ol, F-81106 Castres, France
Titolo Testata:
BRITISH JOURNAL OF PHARMACOLOGY
fascicolo: 7, volume: 130, anno: 2000,
pagine: 1505 - 1512
SICI:
0007-1188(200008)130:7<1505:DLCRBW>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
HAMSTER OVARY CELLS; ADRENERGIC-RECEPTORS; DIRECTED MUTAGENESIS; ADENYLATE-CYCLASE; AGONISTS; ANTAGONISTS; INHIBITION; PATHWAYS;
Keywords:
recombinant human alpha(2A) AR and G(alpha 15) protein; fusion protein; mutagenesis; Ca2+ response; intrinsic ligand activity; diverse signalling;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
24
Recensione:
Indirizzi per estratti:
Indirizzo: Pauwels, PJ Ctr Rech Pierre Fabre, Dept Cellular & Mol Biol, 17 Ave Jean Moulin, F-81106 Castres, France Ctr Rech Pierre Fabre 17 Ave Jean Moulin Castres France F-81106
Citazione:
P.J. Pauwels e F.C. Colpaert, "Disparate ligand-mediated Ca2+ responses by wild-type, mutant Ser(200)Ala and Ser(204)Ala alpha(2A)-adrenoceptor: G(alpha 15) fusion proteins: evidence for multiple ligand-activation binding sites", BR J PHARM, 130(7), 2000, pp. 1505-1512

Abstract

1 Ligand:receptor interactions were analysed at wt, mutant Ser(200)Ala andSer(204)Ala alpha(2A) ARs by measuring Ca2+ responses in CHO-K1 cells either by co-expression with a G(alpha 15) protein or at a receptor:G(alpha 15)protein stoichiometry of 1.0 using fusion proteins.2 The magnitude of the UK 14304-mediated Ca2+ response as elicited by a G(alpha 15) protein was largest with both mutant Ser(200)Ala and Ser204Ala alpha(2A)ARs compared to the wt alpha(2A) AR in the co-expression and fusion protein experiments.3 The activation profiles of the wt and both mutant alpha(2A) ARs as analysed by a series of alpha(2) AR agonists differed. d-Medetomidine and clonidine appeared most efficacious at the Ser(204)Ala alpha(2A) AR, whereas oxymetazoline was also partially active at the Ser(200)Ala alpha(2A) AR. Talipexole was silent at both mutant alpha(2A) ARs. The intrinsic activity of (-)-adrenaline was either absent or partial at the Ser204Ala and Ser200Ala alpha(2A) AR, respectively. This latter observation is related to its lower binding affinity for both mutant alpha(2A) ARs.4 Ligands characterized as antagonists at wt and Ser(200)Ala alpha(2A) ARsdemonstrated either no intrinsic activity (i.e., RX 811059) or positive efficacy with a different rank order of maximal response at the Ser(204)Ala alpha(2A) AR (atipamezole = SKF 86466 = idazoxan > dexefaroxan) than Asp(79)Asn alpha(2A) AR (atipamezole > idazoxan similar or equal to SKF 86466 > dexefaroxan) and Thr(373)Lys alpha(2A) AR (SKF 86466 > atipamezole - idazoxan> dexefaroxan). These effects were only observed in the coexpression experiments at concentrations in line with their binding affinities.5 In conclusion, these Ca2+ data suggest that multiple activation binding sites exist for these ligands at the alpha(2A) AR, and that their activation may be affected in different ways by the mutations being investigated.

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Documento generato il 10/04/20 alle ore 15:06:54