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Titolo:
Reciprocal modulation of alpha(2A)-adrenoceptor and G(alpha o) protein states as determined by carboxy-terminal mutagenesis of a G(alpha o) protein
Autore:
Wurch, T; Okuda, J; Pauwels, PJ;
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:
MOLECULAR PHARMACOLOGY
fascicolo: 4, volume: 60, anno: 2001,
pagine: 666 - 673
SICI:
0026-895X(200110)60:4<666:RMOAAG>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
HAMSTER OVARY CELLS; ADRENERGIC-RECEPTORS; COUPLED RECEPTORS; MEDIATED ACTIVATION; ALPHA-SUBUNIT; BINDING; G(S); TRAFFICKING; SPECIFICITY; G(S-ALPHA);
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
33
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:
T. Wurch et al., "Reciprocal modulation of alpha(2A)-adrenoceptor and G(alpha o) protein states as determined by carboxy-terminal mutagenesis of a G(alpha o) protein", MOLEC PHARM, 60(4), 2001, pp. 666-673

Abstract

The C-terminal portion of G(alpha) proteins plays a key role in their selective activation by cognate receptors. alpha (2A)-Adrenoceptors (alpha (2A)-ARs) can differentially inhibit or stimulate adenylyl cyclases by the activation of distinct G(i/o) and G(s) protein families. The implication of theC-terminal portion of G(alphao) and G(alphas) proteins in their activationby alpha (2A)-ARs was analyzed by constructing mutant G(alphao) proteins in which each of the last five amino acid positions were exchanged for thosecorresponding to a G(alphas) protein. Agonist-dependent, pertussis toxin-resistant binding of guanosine 5'-O-(3-[S-35]thio)triphosphate (S-35]GTP gammaS) revealed that the degree of positive efficacy of clonidine was highly dependent on the presence of a G(alphao) protein-derived Gly amino acid as the -3 residue at the C-terminal portion of the protein. In contrast, antagonist properties for clonidine were observed for those mutants carrying a G(alphas) protein-derived Glu residue at this position. (-)-Epinephrine yielded almost similar maximal [S-35]GTP gammaS binding responses, but its potency was decreased 22- to 150-fold at the -3 Glu containing mutant G(alphao)proteins compared with those mutants containing a Gly. A 9- to 39-fold increase in the alpha (2A)-AR agonist equilibrium dissociation constants further reflected changes in the G(alpha) protein-induced alpha (2A)-AR state mediated by the specific Gly to Glu mutation in the C-terminal portion of theG(alpha) protein. The present data emphasize the unique role of the -3 position at the G(alpha) protein C-terminal portion, independent of its surrounding peptidic environment, in constraining a structure favorable for activated receptor interaction and transmission of the mutation-induced conformational change from the G(alphao) protein to the alpha (2A)-AR.

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Documento generato il 02/04/20 alle ore 16:59:43