title: Different domains of the ORL1 and kappa-opioid receptors are involved in recognition of nociceptin and dynorphin A.
abstract: In order to gain further insight into the functional architecture of structurally related G protein-coupled receptors, the ORL1 (nociceptin) and opioid receptors, we have constructed chimeras of ORL1 and mu-, delta- and kappa-opioid receptors, and compared their binding and functional properties with those of the parent receptors. We find in particular that a ORL1-kappa-opioid (O-K) hybrid construct has retained high affinity for non-type-selective opiate ligands, and has acquired the ability to bind and respond to enkephalins and mu- and/or delta-opioid receptor-selective enkephalins analogs, thus behaving like a 'universal' opioid receptor. Most significantly however, whilst the ORL1 and kappa-opioid receptors display high binding preference (KD 0.1 vs. 100 nM) for their respective endogenous ligands, nociceptin and dynorphin A, the O-K chimeric receptor binds both nociceptin and dynorphin A, with high affinity (KD < 1 nM). Together, these data (i) add weight to the hypothesis that the extracellular loops of opioid receptors act as a filter for ligand selection, and (ii) demonstrate that different domains of the ORL1 and kappa-opioid receptors are involved in recognition of their endogenous peptide ligands.
authors.affiliation: Neuropharmacologie Moléculaire, Institut de Pharmacologie et de Biologie Structurale, CNRS UPR 9062, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Lapalu
authors.forename: C
authors.initials: C
authors.lastname: Moisand
authors.forename: J L
authors.initials: JL
authors.lastname: Butour
authors.forename: C
authors.initials: C
authors.lastname: Mollereau
authors.forename: J C
authors.initials: JC
authors.lastname: Meunier
mesh_terms: D000818:Animals; D016466:CHO Cells; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP; D004399:Dynorphins / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D009292:Narcotic Antagonists / Q000737:chemistry; D009294:Narcotics / Q000737:chemistry; D018847:Opioid Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011957:Receptors, Opioid / Q000737:chemistry* / Q000235:genetics; D017473:Receptors, Opioid, kappa / Q000737:chemistry* / Q000235:genetics; D011993:Recombinant Fusion Proteins; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D005576:Colforsin; D000242:Cyclic AMP; D004399:Dynorphins; D008024:Ligands; D009292:Narcotic Antagonists; D009294:Narcotics; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D011993:Recombinant Fusion Proteins; D000094942:Nociceptin Receptor; D000097629:Nociceptin