Heterodimerization of opioid receptor-like 1 and micro-opioid receptors impairs the potency of micro receptor agonist.

摘要

Nociceptin activation of ORL1 (opioid receptor-like 1 receptor) has been shown to antagonize micro receptor-mediated analgesia at the supraspinal level. ORL1 and micro-opioid receptor (microR) 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 micro receptor. Thus, it is hypothesized that ORL1 and microR interact to form the heterodimer and that ORL1/microR heterodimerization may be one molecular basis for ORL1-mediated antiopioid effects in the brain. To test this hypothesis, myc-tagged ORL1 and HA-tagged microR are co-expressed in human embryonic kidney (HEK) 293 cells. Co-immunoprecipitation experiments demonstrate that ORL1 dimerizes with microR and that intracellular C-terminal tails of ORL1 and microR are required for the formation of ORL1/microR heterodimer. Second messenger assays further indicate that formation of ORL1/microR heterodimer selectively induces cross-desensitization of microR 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/microR heterodimerization and the resulting impairment of micro receptor-activated signaling pathways may contribute to ORL1-mediated antiopioid effects in the brain.