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Titolo:
Functional inactivation of the nociceptin receptor by alanine substitutionof glutamine 286 at the c terminus of transmembrane segment VI: Evidence from a site-directed mutagenesis study of the ORL1 receptor transmembrane-binding domain
Autore:
Mouledous, L; Topham, CM; Moisand, C; Mollereau, C; Meunier, JC;
Indirizzi:
Inst Pharmacol & Biol Struct, CNRS, UPR 9062, F-31077 Toulouse 4, France Inst Pharmacol & Biol Struct Toulouse France 4 -31077 Toulouse 4, France
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 3, volume: 57, anno: 2000,
pagine: 495 - 502
SICI:
0026-895X(200003)57:3<495:FIOTNR>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
DELTA-OPIOID RECEPTOR; PROTEIN-COUPLED RECEPTORS; ORPHANIN FQ RECEPTOR; DYNORPHIN-A; INTRINSIC ACTIVITY; RECOGNITION; ANTAGONIST; PEPTIDE; NEUROPEPTIDE; ACTIVATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Meunier, JC Inst Pharmacol & Biol Struct, CNRS, UPR 9062, 205 Route Narbonne, F-31077 Toulouse 4, France Inst Pharmacol & Biol Struct 205 Route Narbonne Toulouse France 4
Citazione:
L. Mouledous et al., "Functional inactivation of the nociceptin receptor by alanine substitutionof glutamine 286 at the c terminus of transmembrane segment VI: Evidence from a site-directed mutagenesis study of the ORL1 receptor transmembrane-binding domain", MOLEC PHARM, 57(3), 2000, pp. 495-502

Abstract

A site-directed mutagenesis approach has been used to gain insight into the molecular events whereby the heptadecapeptide nociceptin binds and activates the opioid receptor-like 1 (ORL1) receptor, a G protein-coupled receptor. Alanine mutation, in the human ORL1 receptor, of transmembrane amino acid residues that are conserved in opioid receptors, Asp(130) and Tyr(131) intransmembrane segment (TM) III, Phe(220) and Phe(224) in TM V, and Trp(276) in TM VI, yields mutant receptors with reduced affinity, and proportionally decreased reactivity, toward nociceptin. Least to most deleterious in this respect are Ala substitutions of Phe(220) similar to W276A < Tyr(131) <<Phe(224) less than or equal to Asp(130). The dramatic effects of the D130Amutation on nociceptin binding and activity are not reversed in the D130N mutant, whereas those of the Y131A mutation are totally suppressed in Y131F. This suggests that a negative charge at position 130, and a phenyl ring at position 131 in TM III, are critical for occupancy and/or activation of the receptor by nociceptin. Alanine replacement of glutamine 286, located atthe C terminus of TM VI, yields a mutant receptor that binds nociceptin with nearly the same affinity as does the wild-type receptor (K-d values of 0.13 and 0.22 nM, respectively) but, unlike the latter, is unable to mediatenociceptin inhibition of forskolin-induced cAMP synthesis in recombinant Chinese hamster ovary cells (ED50 > 10,000 nM compared with 0.8 nM at the wild-type receptor). In all respects, this mutant receptor appears to be functionally inactive, indicating that residue Gln 286 may play a pivotal role in ORL1 receptor-mediated transduction of the nociceptin signal.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 09/08/20 alle ore 23:01:44