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Titolo:
Ligand-receptor interactions as controlled by wild-type and mutant Thr(370)Lys alpha(2B)-adrenoceptor-G(alpha 15) fusion proteins
Autore:
Pauwels, PJ; Tardif, S; Finana, F; Wurch, T; 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:
JOURNAL OF NEUROCHEMISTRY
fascicolo: 1, volume: 74, anno: 2000,
pagine: 375 - 384
SICI:
0022-3042(200001)74:1<375:LIACBW>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
GAMMA-S BINDING; BETA(2)-ADRENERGIC RECEPTOR; TRANSMEMBRANE DOMAIN; ADRENERGIC-RECEPTORS; CELL-LINES; SUBTYPE; ACTIVATION; EFFICACY; MUTAGENESIS; STIMULATION;
Keywords:
recombinant human alpha(2B)-adrenoceptor; fusion protein; mutagenesis of BBXXB motif; Ca2+ response; intrinsic ligand activity;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
43
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 et al., "Ligand-receptor interactions as controlled by wild-type and mutant Thr(370)Lys alpha(2B)-adrenoceptor-G(alpha 15) fusion proteins", J NEUROCHEM, 74(1), 2000, pp. 375-384

Abstract

Fusion proteins were constructed between either a wild-type or mutant Thr(370)Lys alpha(2B)-adrenoceptor (alpha(2B) AR) and a mouse G(alpha 15) protein to analyze ligand-receptor interactions at a receptor/G(alpha 15) protein density ratio of 1. Activation of the wild-type alpha(2B) AR-G(alpha 15) fusion protein in CHO-K1 cells by (-)-adrenaline induced a time- and concentration-dependent (pEC(50) = 7.37 +/- 0.13) increase in the intracellular Ca2+ concentration, which could be antagonized by RX 811059 (pK(B) = 7.55 +/- 0.15). Whereas d-medetomidine and oxymetazoline were as efficacious agonists as (-)-adrenaline, the following ligands displayed partial agonist properties: BRL 44408 < atipamezole < clonidine < UK 14304 < BHT 920. A comparison with the mutant Thr(370)Lys alpha(2B) AR-G(alpha 15) fusion protein displayed similar Ca2+ kinetics and a ligand-mediated receptor activation profile characterized by higher potencies and greater maximal Ca2+ responses for the ligands being investigated, including the putative antagonists dexefaroxan and idazoxan. RX 811059 and RX 821002 remained silent. Similar conclusions could be made on enhancement of the ligands' intrinsic activities by coexpression of the mutant Thr(370)Lys alpha(2B) AR With either a G(alpha 15) or G(alpha O) Cys(351)Ile protein. The Thr(370)Lys alpha(2B) AR-G(alpha)protein interactions may modify the tertiary structure of the mutant receptor in such a way that some putative alpha(2) AR antagonists are capable ofstabilizing an active receptor conformation, thereby generating positive efficacy.

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Documento generato il 30/05/20 alle ore 02:29:12