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Review ArticleReview Article

Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes

Nicola J. Smith and Graeme Milligan
David Sibley, ASSOCIATE EDITOR
Pharmacological Reviews December 2010, 62 (4) 701-725; DOI: https://doi.org/10.1124/pr.110.002667
Nicola J. Smith
Molecular Pharmacology Group, Neuroscience and Molecular Pharmacology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
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Graeme Milligan
Molecular Pharmacology Group, Neuroscience and Molecular Pharmacology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
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David Sibley
Molecular Pharmacology Group, Neuroscience and Molecular Pharmacology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
Roles: ASSOCIATE EDITOR
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Abstract

For many years seven transmembrane domain G protein-coupled receptors (GPCRs) were thought to exist and function exclusively as monomeric units. However, evidence both from native cells and heterologous expression systems has demonstrated that GPCRs can both traffic and signal within higher-order complexes. As for other protein-protein interactions, conformational changes in one polypeptide, including those resulting from binding of pharmacological ligands, have the capacity to alter the conformation and therefore the response of the interacting protein(s), a process known as allosterism. For GPCRs, allosterism across homo- or heteromers, whether dimers or higher-order oligomers, represents an additional topographical landscape that must now be considered pharmacologically. Such effects may offer the opportunity for novel therapeutic approaches. Allosterism at GPCR heteromers is particularly exciting in that it offers additional scope to provide receptor subtype selectivity and tissue specificity as well as fine-tuning of receptor signal strength. Herein, we introduce the concept of allosterism at both GPCR homomers and heteromers and discuss the various questions that must be addressed before significant advances can be made in drug discovery at these GPCR complexes.

Footnotes

  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.110.002667.

  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 62 (4)
Pharmacological Reviews
Vol. 62, Issue 4
1 Dec 2010
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Review ArticleReview Article

Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes

Nicola J. Smith and Graeme Milligan
Pharmacological Reviews December 1, 2010, 62 (4) 701-725; DOI: https://doi.org/10.1124/pr.110.002667

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Review ArticleReview Article

Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes

Nicola J. Smith and Graeme Milligan
Pharmacological Reviews December 1, 2010, 62 (4) 701-725; DOI: https://doi.org/10.1124/pr.110.002667
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  • Article
    • Abstract
    • I. Introduction
    • II. Allosterism
    • III. Evidence for Allosterism at G Protein-Coupled Receptor Dimers
    • IV. Exploring the Expanded Pharmacological Landscape: The Challenge for Drug Discovery
    • V. Concluding Remarks
    • VI. Glossary
    • Acknowledgments.
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