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Research ArticleCELLULAR AND MOLECULAR

Endogenous Regulator of G Protein Signaling Proteins Suppress Gαo-Dependent, μ-Opioid Agonist-Mediated Adenylyl Cyclase Supersensitization

Mary J. Clark, Richard R. Neubig and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 215-222; DOI: https://doi.org/10.1124/jpet.103.064824
Mary J. Clark
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Richard R. Neubig
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John R. Traynor
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Abstract

Chronic μ-opioid agonist treatment leads to dependence with withdrawal on removal of agonist. At the cellular level withdrawal is accompanied by a supersensitization of adenylyl cyclase, an effect that requires inhibitory Gα proteins. Inhibitory Gα protein action is modulated by regulator of G protein signaling (RGS) proteins that act as GTPase activating proteins and reduce the lifetime of Gα-GTP. In this article, we use C6 glioma cells expressing the rat μ-opioid receptor (C6μ) to examine the hypothesis that Gαo alone can mediate μ-opioid agonist induced adenylyl cyclase supersensitivity and that endogenous RGS proteins serve to limit the extent of this supersensitization. C6μ cells were stably transfected with pertussis toxin (PTX)-insensitive Gαo that was either sensitive or insensitive to endogenous RGS proteins. Cells were treated with PTX to uncouple endogenous Gα proteins followed by exposure to the μ-opioid agonists [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin or morphine. Supersensitization was observed in cells expressing wild-type Gα, but this was lost on PTX treatment. In cells expressing PTX-insensitive Gαo supersensitization was recovered, confirming that Gαo alone can support supersensitization. In cells expressing the RGS-insensitive mutant Gαo, there was a greater degree of supersensitization and the concentration of μ-agonist needed to achieve half-maximal supersensitization was reduced by 10-fold. The amount of supersensitization seen did not directly relate to the degree of acute inhibition of adenylyl cyclase. These results demonstrate a role for Gαo in adenylyl cyclase supersensitization after μ-agonist exposure and show that this action is modulated by endogenous RGS proteins.

Footnotes

  • This study was supported by Grants DA04087 (to J.R.T.) and GM39561 (to R.R.N.). Portions of these data have been published in abstract form in FASEB J. 17:A218, abstract 145.6.

  • DOI: 10.1124/jpet.103.064824.

  • ABBREVIATIONS: PTX, pertussis toxin; GIRK, G protein-gated inwardly rectifying K+ channel; MAPK, mitogen-activated protein kinase; RGS, regulator of G protein signaling; GAP, GTPase-activating protein; HEK, human embryonic kidney; ERK, extracellular signal-regulated kinase; IBMX, 3-isobutyl-1-methylxanthine; DAMGO, [d-Ala2,MePhe4,Gly5-ol]enkephalin; PTXi, pertussis toxin-insensitive.

    • Received December 22, 2003.
    • Accepted March 9, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
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Research ArticleCELLULAR AND MOLECULAR

Endogenous Regulator of G Protein Signaling Proteins Suppress Gαo-Dependent, μ-Opioid Agonist-Mediated Adenylyl Cyclase Supersensitization

Mary J. Clark, Richard R. Neubig and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 215-222; DOI: https://doi.org/10.1124/jpet.103.064824

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Research ArticleCELLULAR AND MOLECULAR

Endogenous Regulator of G Protein Signaling Proteins Suppress Gαo-Dependent, μ-Opioid Agonist-Mediated Adenylyl Cyclase Supersensitization

Mary J. Clark, Richard R. Neubig and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 215-222; DOI: https://doi.org/10.1124/jpet.103.064824
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