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Refining Efficacy: Allosterism and Bias in G Protein-Coupled Receptor Signaling

  • Louis M. LuttrellEmail author
  • Terry P. Kenakin
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 756)

Abstract

Receptors on the surface of cells function as conduits for information flowing between the external environment and the cell interior. Since signal transduction is based on the physical interaction of receptors with both extracellular ligands and intracellular effectors, ligand binding must produce conformational changes in the receptor that can be transmitted to the intracellular domains accessible to G proteins and other effectors. Classical models of G protein-coupled receptor (GPCR) signaling envision receptor conformations as highly constrained, wherein receptors exist in equilibrium between single “off” and “on” states distinguished by their ability to activate effectors, and ligands act by perturbing this equilibrium. In such models, ligands can be classified based upon two simple parameters; affinity and efficacy, and ligand activity is independent of the assay used to detect the response. However, it is clear that GPCRs assume multiple conformations, any number of which may be capable of interacting with a discrete subset of possible effectors. Both orthosteric ligands, molecules that occupy the natural ligand-binding pocket, and allosteric modulators, small molecules or proteins that contact receptors distant from the site of ligand binding, have the ability to alter the conformational equilibrium of a receptor in ways that affect its signaling output both qualitatively and quantitatively. In this context, efficacy becomes pluridimensional and ligand classification becomes assay dependent. A more complete description of ligand–receptor interaction requires the use of multiplexed assays of receptor activation and screening assays may need to be tailored to detect specific efficacy profiles.

Key words

Agonist G protein-coupled receptor Heterotrimeric guanine nucleotide-binding protein Pharmaceutical chemistry Pharmacodynamics Signal transduction 

Notes

Acknowledgments

The Luttrell laboratory is supported by National Institutes of Health Grant DK55524 and the Research Service of the Charleston SC Veterans Affairs Medical Center.

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Departments of Medicine and Biochemistry & Molecular BiologyMedical University of South CarolinaCharlestonUSA
  2. 2.Charleston VA Medical CenterCharlestonUSA
  3. 3.Department of PharmacologyUniversity of North Carolina, School of MedicineChapel HillUSA

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