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Research ArticleCELLULAR AND MOLECULAR

Relationship between Rate and Extent of G Protein Activation: Comparison between Full and Partial Opioid Agonists

John R. Traynor, Mary J. Clark and Ann E. Remmers
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 157-161; DOI: https://doi.org/10.1124/jpet.300.1.157
John R. Traynor
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Mary J. Clark
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Ann E. Remmers
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Abstract

Opioid agonists acting at their receptors alter intracellular events by initiating activation of various types of Gi/Go proteins. This can be measured by the binding of the stable GTP analog [35S]guanosine-5′-O-(3-thio)triphosphate ([35S]GTPγS). In this study agonist efficacy is defined by the degree to which an opioid stimulates the binding of [35S]GTPγS. This allows for a definition of full and partial agonists; a full agonist causing a greater stimulation of [35S]GTPγS binding than a partial agonist. The hypothesis that the rate of agonist-stimulated [35S]GTPγS binding is dependent upon agonist efficacy was tested using membranes from C6 glioma cells expressing μ- or δ-opioid receptors. At maximal concentrations the rate of agonist-stimulated [35S]GTPγS binding followed the efficacy of μ-agonists in stimulating [35S]GTPγS binding, i.e., [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin > morphine > meperidine > butorphanol > nalbuphine. At submaximal concentrations of μ- or δ-full agonists the [35S]GTPγS association rate was also reduced, such that the rate of [35S]GTPγS binding correlated with the extent of [35S]GTPγS bound, whether this binding was stimulated by a full agonist or a partial agonist. Agonists also stimulated [35S]GTPγS dissociation, showing that binding of this stable nucleotide was reversible. Comparison of the δ-agonists [d-Ser2,Leu5]-enkephalin-Thr and (±)-4-((α-R*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxylbenzyl)-N,N-diethylbenzamide, a compound with slow dissociation kinetics, showed the measured rate of G protein activation was not influenced by the agonist switching between receptors. The results are consistent with the idea that the active state(s) of the receptor induced by full or partial agonists is the same, but the number of activated receptors determines the rate of G protein activation.

Footnotes

  • This work was supported by National Institutes of Health Grants DA 00254 and DA 04087.

  • Abbreviations

    GTPγS
    guanosine-5′-O-(3-thio)triphosphate
    C6μ
    C6 glioma cell line stably expressing the rat μ-opioid receptor
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    DSLET
    [d-Ser2,Leu5]-enkephalin-Thr
    C6δ
    C6 glioma cell line stably expressing the rat δ-opioid receptor
    ddH2O
    double-distilled water
    BW373U86
    (±)-4-((α-R*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxylbenzyl)-N,N-diethylbenzamide
    • Received July 31, 2001.
    • Accepted October 5, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
    Vol. 300, Issue 1
    1 Jan 2002
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    Research ArticleCELLULAR AND MOLECULAR

    Relationship between Rate and Extent of G Protein Activation: Comparison between Full and Partial Opioid Agonists

    John R. Traynor, Mary J. Clark and Ann E. Remmers
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 157-161; DOI: https://doi.org/10.1124/jpet.300.1.157

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    Research ArticleCELLULAR AND MOLECULAR

    Relationship between Rate and Extent of G Protein Activation: Comparison between Full and Partial Opioid Agonists

    John R. Traynor, Mary J. Clark and Ann E. Remmers
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 157-161; DOI: https://doi.org/10.1124/jpet.300.1.157
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