Different domains of the ORL1 and κ‐opioid receptors are involved in recognition of nociceptin and dynorphin A

FEBS Letters

Moisand, Christiane¹  Mollereau, Catherine¹  Butour, Jean-Luc¹  Meunier, Jean-Claude¹  Lapalu, Sophie¹ 

[1]Neuropharmacologie Moléculaire, Institut de Pharmacologie et de Biologie Structurale, C.N.R.S. UPR 9062, 205 route de Narbonne, 31077 Toulouse Cedex 4, France

关键词: Non-opioid–opioid hybrid receptor;    Gain-of-function protein engineering;    Opioid peptide;    Structure-function relationship;    hORL1;    human opioid receptor-like 1 receptor;    hMOR1;    hDOR1 and hKOR1;    human μ-;    δ- and κ-opioid receptor;    respectively;    O-M;    O-D and O-K;    hORL1-(1–133)–hMOR1-(152–400);    -hDOR1-(131–372) and -hKOR1-(142–380) chimeric receptors;    respectively;    M-O;    D-O and K-O;    hMOR1-(1–151)–hORL1-(134–370);    hDOR1-(1–130)- and -hKOR1-(1–141)- chimeric receptors;    respectively;    DAGO;    [d-Ala2;    N-Me-Phe4;    Gly-ol5]enkephalin;    DTLET;    [d-Thr2;    Leu5;    Thr6]enkephalin;    U-50488;    trans-(1S;    2S)-3;    4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide;    EKC;    ethylketocyclazocine;    nor-BNI;    nor-binaltorphimine;   

DOI  :  10.1016/S0014-5793(98)00452-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 μ-, δ- and κ-opioid receptors, and compared their binding and functional properties with those of the parent receptors. We find in particular that a ORL1–κ-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 μ- and/or δ-opioid receptor-selective enkephalins analogs, thus behaving like a `universal' opioid receptor. Most significantly however, whilst the ORL1 and κ-opioid receptors display high binding preference (K _D 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 (K _D<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 κ-opioid receptors are involved in recognition of their endogenous peptide ligands.

【 授权许可】

Unknown