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Research ArticleCELLULAR AND MOLECULAR

Differential Effects of Agonists on Adenylyl Cyclase Superactivation Mediated by the κ Opioid Receptors: Adenylyl Cyclase Superactivation Is Independent of Agonist-Induced Phosphorylation, Desensitization, Internalization, and Down-Regulation

Yulin Wang, Jian-Guo Li, Peng Huang, Wei Xu and Lee-Yuan Liu-Chen
Journal of Pharmacology and Experimental Therapeutics December 2003, 307 (3) 1127-1134; DOI: https://doi.org/10.1124/jpet.103.055814
Yulin Wang
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Jian-Guo Li
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Peng Huang
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Wei Xu
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Lee-Yuan Liu-Chen
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Abstract

Prolonged activation of opioid receptors followed by agonist removal leads to adenylyl cyclase (AC) superactivation. In this study, we examined in CHO cells stably expressing the human or rat κ opioid receptor (hkor or rkor) whether agonists had differential abilities to induce AC superactivation and whether the hkor and rkor exhibited differential AC superactivation. Pretreatment of the hkor with (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate (U50,488H) induced AC superactivation in a time- and dose-dependent manner, reaching a plateau at 4 h and 0.1 μM. The extents of AC superactivation after a 4-h pretreatment of the hkor with saturating concentrations of agonists were in the order of the full agonists U50,488H, dynorphin A(1–17), (±)-ethylketocyclazocine, etorphine, and U69,593 > the high-efficacy partial agonist nalorphine > the low-efficacy partial agonists nalbuphine, morphine, and pentazocine. Interestingly, the full agonist levorphanol caused much lower AC superactivation than other full agonists and reduced the AC superactivation induced by U50,488H and dynorphin A(1–17) in a dose-dependent manner. The order of relative efficacies of agonists in causing AC superactivation mediated by the rkor was similar to that mediated by the hkor and the extents of AC superactivation were slightly lower. Because the rkor does not undergo U50,488H (1 μM)-induced phosphorylation, desensitization, internalization, and down-regulation in these cells, the degree of AC superactivation is independent of these processes. This is among the first reports to demonstrate that relative efficacies of agonists in causing AC superactivation generally correlated with those in activating G proteins and a full agonist reduced AC superactivation induced by another full agonist.

Footnotes

  • This work was supported by National Institutes of Health Grants DA04745, DA11263, and DA13429.

  • DOI: 10.1124/jpet.103.055814.

  • ABBREVIATIONS. AC, adenylyl cyclase; U50,488H, (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate; hkor, human κ opioid receptor; rkor, rat κ opioid receptor; CHO cells, Chinese hamster ovary; CHO-FLAG-hkor, clonal CHO cell lines stably expressing the FLAG-tagged human κ opioid receptor; CHO-FLAG-rkor, clonal CHO cell lines stably expressing the FLAG-tagged rat κ opioid receptor; FLAG-hkor, FLAG-tagged human κ opioid receptor; FLAG-rkor, FLAG-tagged rat κ opioid receptor; HEK, human embryonic kidney; GTPγS, guanosine 5′-O-(3-thio)triphosphate; IBMX, 1-methyl-3-isobutylxanthine; (±)-EKC, (±)-ethylketocyclazocine; DAMGO, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; U69,593, (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-benzeneacetamide.

    • Received June 16, 2003.
    • Accepted September 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 3
1 Dec 2003
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Research ArticleCELLULAR AND MOLECULAR

Differential Effects of Agonists on Adenylyl Cyclase Superactivation Mediated by the κ Opioid Receptors: Adenylyl Cyclase Superactivation Is Independent of Agonist-Induced Phosphorylation, Desensitization, Internalization, and Down-Regulation

Yulin Wang, Jian-Guo Li, Peng Huang, Wei Xu and Lee-Yuan Liu-Chen
Journal of Pharmacology and Experimental Therapeutics December 1, 2003, 307 (3) 1127-1134; DOI: https://doi.org/10.1124/jpet.103.055814

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Research ArticleCELLULAR AND MOLECULAR

Differential Effects of Agonists on Adenylyl Cyclase Superactivation Mediated by the κ Opioid Receptors: Adenylyl Cyclase Superactivation Is Independent of Agonist-Induced Phosphorylation, Desensitization, Internalization, and Down-Regulation

Yulin Wang, Jian-Guo Li, Peng Huang, Wei Xu and Lee-Yuan Liu-Chen
Journal of Pharmacology and Experimental Therapeutics December 1, 2003, 307 (3) 1127-1134; DOI: https://doi.org/10.1124/jpet.103.055814
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