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

Hung Li Wang, Chia Yu Hsu, Pei Chen Huang, Yo Li Kuo, Allen Hon Lun Li, Tu Hsueh Yeh, An Swe Tso, Ying Ling Chen

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

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-Ala2,N-methyl-Phe4,Glyol5]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.

Original languageEnglish
Pages (from-to)1285-1294
Number of pages10
JournalJournal of Neurochemistry
Volume92
Issue number6
DOIs
Publication statusPublished - Mar 2005
Externally publishedYes

Fingerprint

Opioid Receptors
Brain
Phosphorylation
Enkephalins
Mitogen-Activated Protein Kinase 1
Second Messenger Systems
Mitogen-Activated Protein Kinases
Immunoprecipitation
Adenylyl Cyclases
Analgesia
Neurons
Tail
Amino Acid Sequence
Assays

Keywords

  • μ-opioid receptor
  • DAMGO
  • Nociceptin
  • Opioid receptor-like 1 receptor
  • Receptor heterodimerization

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Heterodimerization of opioid receptor-like 1 and μ-opioid receptors impairs the potency of μ receptor agonist. / Wang, Hung Li; Hsu, Chia Yu; Huang, Pei Chen; Kuo, Yo Li; Li, Allen Hon Lun; Yeh, Tu Hsueh; Tso, An Swe; Chen, Ying Ling.

In: Journal of Neurochemistry, Vol. 92, No. 6, 03.2005, p. 1285-1294.

Research output: Contribution to journalArticle

Wang, Hung Li ; Hsu, Chia Yu ; Huang, Pei Chen ; Kuo, Yo Li ; Li, Allen Hon Lun ; Yeh, Tu Hsueh ; Tso, An Swe ; Chen, Ying Ling. / Heterodimerization of opioid receptor-like 1 and μ-opioid receptors impairs the potency of μ receptor agonist. In: Journal of Neurochemistry. 2005 ; Vol. 92, No. 6. pp. 1285-1294.
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abstract = "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-Ala2,N-methyl-Phe4,Glyol5]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.",
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AU - Wang, Hung Li

AU - Hsu, Chia Yu

AU - Huang, Pei Chen

AU - Kuo, Yo Li

AU - Li, Allen Hon Lun

AU - Yeh, Tu Hsueh

AU - Tso, An Swe

AU - Chen, Ying Ling

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N2 - 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-Ala2,N-methyl-Phe4,Glyol5]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.

AB - 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-Ala2,N-methyl-Phe4,Glyol5]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.

KW - μ-opioid receptor

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KW - Receptor heterodimerization

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