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Research ArticleArticle

G Protein-Coupled Receptor Heteromerization: A Role in Allosteric Modulation of Ligand Binding

Ivone Gomes, Adriaan P. IJzerman, Kai Ye, Emeline L. Maillet and Lakshmi A. Devi
Molecular Pharmacology June 2011, 79 (6) 1044-1052; DOI: https://doi.org/10.1124/mol.110.070847
Ivone Gomes
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Adriaan P. IJzerman
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Kai Ye
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Emeline L. Maillet
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Lakshmi A. Devi
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Abstract

It is becoming increasingly recognized that G protein-coupled receptors physically interact. These interactions may provide a mechanism for allosteric modulation of receptor function. In this study, we examined this possibility by using an established model system of a receptor heteromer consisting of μ and δ opioid receptors. We examined the effect of a number of μ receptor ligands on the binding equilibrium and association and dissociation kinetics of a radiolabeled δ receptor agonist, [3H]deltorphin II. We also examined the effect of δ receptor ligands on the binding equilibrium and association and dissociation kinetics of a radiolabeled μ receptor agonist, [3H][d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin ([3H]DAMGO). We show that μ receptor ligands are capable of allosterically enhancing δ receptor radioligand binding and vice versa. Thus, there is strong positive cooperativity between the two receptor units with remarkable consequences for ligand pharmacology. We find that the data can be simulated by adapting an allosteric receptor model previously developed for small molecules, suggesting that the ligand-occupied protomers function as allosteric modulators of the partner receptor's activity.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by National Institutes of Health National Institute on Drug Abuse [Grants DA08863, DA019251] (to L.A.D.); and by the Dutch Top Institute Pharma project [Grant D1-105] (to A.P.IJ.)

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.070847.

  • ABBREVIATIONS:

    GPCR
    G protein-coupled receptor
    OR
    opioid receptor
    TIPPψ
    Tyr-Ticψ(CH2NH)-Phe-Phe
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    deltorphin II
    Tyr-d-Ala-Phe-Glu-Val-Val-Gly
    CTOP
    d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2
    BNTX
    7-benzylidenenaltrexone maleate
    CTAP
    d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2
    CHO
    Chinese hamster ovary
    ICI 174,864
    N,N-diallyl-Tyr-Aib-Aib-Phe-Leu
    SNC80
    (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide
    ANOVA
    analysis of variance
    WIN55212-2
    (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone.

  • Received December 28, 2010.
  • Accepted March 17, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (6)
Molecular Pharmacology
Vol. 79, Issue 6
1 Jun 2011
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Research ArticleArticle

G Protein-Coupled Receptor Heteromerization: A Role in Allosteric Modulation of Ligand Binding

Ivone Gomes, Adriaan P. IJzerman, Kai Ye, Emeline L. Maillet and Lakshmi A. Devi
Molecular Pharmacology June 1, 2011, 79 (6) 1044-1052; DOI: https://doi.org/10.1124/mol.110.070847

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Research ArticleArticle

G Protein-Coupled Receptor Heteromerization: A Role in Allosteric Modulation of Ligand Binding

Ivone Gomes, Adriaan P. IJzerman, Kai Ye, Emeline L. Maillet and Lakshmi A. Devi
Molecular Pharmacology June 1, 2011, 79 (6) 1044-1052; DOI: https://doi.org/10.1124/mol.110.070847
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