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Heterodimerization of opioid receptor‐like 1 and µ‐opioid receptors impairs the potency of µ receptor agonist
Author(s) -
Wang HungLi,
Hsu ChiaYu,
Huang PeiChen,
Kuo YoLi,
Li Allen H.,
Yeh TuHsueh,
Tso AnSwe,
Chen YingLing
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02921.x
Subject(s) - nociceptin receptor , damgo , receptor , hek 293 cells , chemistry , microbiology and biotechnology , opioid receptor , enkephalin , signal transduction , μ opioid receptor , agonist , opioid , opioid peptide , biology , biochemistry
Nociceptin activation of ORL1 (opioid receptor‐like 1 receptor) has been shown to antagonize µ receptor‐mediated analgesia at the supraspinal level. ORL1 and µ‐opioid receptor (µR) 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 µ receptor. Thus, it is hypothesized that ORL1 and µR interact to form the heterodimer and that ORL1/µR heterodimerization may be one molecular basis for ORL1‐mediated antiopioid effects in the brain. To test this hypothesis, myc‐tagged ORL1 and HA‐tagged µR are co‐expressed in human embryonic kidney (HEK) 293 cells. Co‐immunoprecipitation experiments demonstrate that ORL1 dimerizes with µR and that intracellular C‐terminal tails of ORL1 and µR are required for the formation of ORL1/µR heterodimer. Second messenger assays further indicate that formation of ORL1/µR heterodimer selectively induces cross‐desensitization of µR 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/µR heterodimerization and the resulting impairment of µ receptor‐activated signaling pathways may contribute to ORL1‐mediated antiopioid effects in the brain.