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Molecular basis of inverse agonism in a G protein–coupled receptor

Nature Chemical Biology volume 1, pages 25–28 (2005)Cite this article

Abstract

G protein–coupled receptors (GPCRs) recognize a wide variety of extracellular ligands to control diverse physiological processes. Compounds that bind to such receptors can either stimulate, fully or partially (full or partial agonists), or reduce (inverse agonists) the receptors' basal activity and receptor-mediated signaling. Various studies have shown that the activation of receptors through binding of agonists proceeds by conformational changes as the receptor switches from a resting to an active state leading to G protein signaling1,2,3,4,5. Yet the molecular basis for differences between agonists and inverse agonists is unclear. These different classes of compounds are assumed to switch the receptors' conformation in distinct ways. It is not known, however, whether such switching occurs along a linear 'on-off' scale or whether agonists and inverse agonists induce different switch mechanisms. Using a fluorescence-based approach to study the α2A-adrenergic receptor (α2AAR), we show that inverse agonists are differentiated from agonists in that they trigger a very distinct mode of a receptor's switch. This switch couples inverse agonist binding to the suppression of activity in the receptor.

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Figure 1: Conformational changes of the α2AAR in response to full and inverse agonists.
Figure 2: Action of inverse agonists on α2AARCFP/YFP.
Figure 3: Characterization of the constitutively active receptor.

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Acknowledgements

We thank M. Bernhard for technical support and K.-N. Klotz and M. Bünemann for comments. The Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie supported this work.

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, Würzburg, D-97078, Germany

    Jean-Pierre Vilardaga & Martin J Lohse

  2. Rudolf-Virchow Center, University of Würzburg, Versbacher Strasse 9, Würzburg, D-97078, Germany

    Ralf Steinmeyer & Greg S Harms

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  1. Jean-Pierre Vilardaga
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  3. Greg S Harms
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Correspondence to Jean-Pierre Vilardaga.

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Supplementary information

Supplementary Fig. 1

Principle of the experiment. (GIF 16 kb)

Supplementary Fig. 2

Chemical structures and names of the diverse ligands used in this study. (GIF 19 kb)

Supplementary Fig. 3

Optical recording of different receptor states from a single cell expressing α2AARCFP/YFP. (GIF 12 kb)

Supplementary Fig. 4

Characterization of the constitutively active α2A-adrenergic receptors. (GIF 29 kb)

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Vilardaga, JP., Steinmeyer, R., Harms, G. et al. Molecular basis of inverse agonism in a G protein–coupled receptor. Nat Chem Biol 1, 25–28 (2005). https://doi.org/10.1038/nchembio705

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