title: Heterodimerization of opioid receptor-like 1 and mu-opioid receptors impairs the potency of micro receptor agonist.
abstract: Nociceptin activation of ORL1 (opioid receptor-like 1 receptor) has been shown to antagonize mu receptor-mediated analgesia at the supraspinal level. ORL1 and mu-opioid receptor (muR) are co-expressed in several subpopulations of CNS neurons involved in regulating pain transmission. The amino acid sequence of ORL1 also shares a high degree of homology with that of mu receptor. Thus, it is hypothesized that ORL1 and muR interact to form the heterodimer and that ORL1/muR heterodimerization may be one molecular basis for ORL1-mediated antiopioid effects in the brain. To test this hypothesis, myc-tagged ORL1 and HA-tagged muR are co-expressed in human embryonic kidney (HEK) 293 cells. Co-immunoprecipitation experiments demonstrate that ORL1 dimerizes with muR and that intracellular C-terminal tails of ORL1 and muR are required for the formation of ORL1/muR heterodimer. Second messenger assays further indicate that formation of ORL1/muR heterodimer selectively induces cross-desensitization of muR and impairs the potency by which [D-Ala(2),N-methyl-Phe(4),Gly-ol(5)]enkephalin (DAMGO) inhibits adenylate cyclase and stimulates p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation. These results provide the evidence that ORL1/muR heterodimerization and the resulting impairment of mu receptor-activated signaling pathways may contribute to ORL1-mediated antiopioid effects in the brain.
authors.affiliation: Department of Physiology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan. hlwns@mail.cgu.edu.tw
authors.forename: Hung-Li
authors.initials: HL
authors.lastname: Wang
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Hsu
authors.forename: Pei-Chen
authors.initials: PC
authors.lastname: Huang
authors.forename: Yo-Li
authors.initials: YL
authors.lastname: Kuo
authors.forename: Allen H
authors.initials: AH
authors.lastname: Li
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.forename: An-Swe
authors.initials: AS
authors.lastname: Tso
authors.forename: Ying-Ling
authors.initials: YL
authors.lastname: Chen
mesh_terms: D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D019281:Dimerization; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D011957:Receptors, Opioid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000094942:Nociceptin Receptor
chemical_list: D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019950:Mitogen-Activated Protein Kinase 1; D000262:Adenylyl Cyclases; D000094942:Nociceptin Receptor