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Research ArticleMinireviews

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

Emma T. van der Westhuizen, Celine Valant, Patrick M. Sexton and Arthur Christopoulos
Journal of Pharmacology and Experimental Therapeutics May 2015, 353 (2) 246-260; DOI: https://doi.org/10.1124/jpet.114.221606
Emma T. van der Westhuizen
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia
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Celine Valant
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia
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Patrick M. Sexton
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia
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Arthur Christopoulos
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia
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Abstract

G protein–coupled receptors (GPCRs) are the largest superfamily of receptors encoded by the human genome, and represent the largest class of current drug targets. Over the last decade and a half, it has become widely accepted that most, if not all, GPCRs possess spatially distinct allosteric sites that can be targeted by exogenous substances to modulate the receptors’ biologic state. Although many of these allosteric sites are likely to serve other (e.g., structural) roles, they nonetheless possess appropriate properties to be serendipitously targeted by synthetic molecules. However, there are also examples of endogenous substances that can act as allosteric modulators of GPCRs. These include not only the obvious example, i.e., the G protein, but also a variety of ions, lipids, amino acids, peptides, and accessory proteins that display different degrees of receptor-specific modulatory effects. This also suggests that some GPCRs may possess true “orphan” allosteric sites for hitherto unappreciated endogenous modulators. Of note, the increasing identification of allosteric modulator lipids, inflammatory peptides, and GPCR-targeted autoantibodies indicates that disease context plays an important role in the generation of putative endogenous GPCR modulators. If an endogenous allosteric substance can be shown to play a role in disease, this could also serve as an impetus to pursue synthetic neutral allosteric ligands as novel therapeutic agents.

Footnotes

    • Received December 3, 2014.
    • Accepted January 30, 2015.
  • E.T.v.d.W. and C.V. contributed equally to this work.

  • Portions of the work cited from the authors’ laboratories were funded by the National Health and Medical Research Council of Australia (NHMRC) [Program Grant APP1055134 and Project Grants APP1026962, APP1084246, and APP1061044]. A.C. and P.M.S. are Principal Research Fellows of the NHMRC.

  • dx.doi.org/10.1124/jpet.114.221606.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 353 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 353, Issue 2
1 May 2015
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Research ArticleMinireviews

Endogenous GPCR Allosteric Modulators

Emma T. van der Westhuizen, Celine Valant, Patrick M. Sexton and Arthur Christopoulos
Journal of Pharmacology and Experimental Therapeutics May 1, 2015, 353 (2) 246-260; DOI: https://doi.org/10.1124/jpet.114.221606

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Research ArticleMinireviews

Endogenous GPCR Allosteric Modulators

Emma T. van der Westhuizen, Celine Valant, Patrick M. Sexton and Arthur Christopoulos
Journal of Pharmacology and Experimental Therapeutics May 1, 2015, 353 (2) 246-260; DOI: https://doi.org/10.1124/jpet.114.221606
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  • Article
    • Abstract
    • Introduction
    • G Proteins as Endogenous Allosteric Modulators
    • GPCR–Accessory Protein Interactions
    • Ions as Allosteric Modulators
    • Lipids as Allosteric Modulators
    • Amino Acids and Peptides as Allosteric Modulators
    • Allosteric Autoantibodies
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