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  • Review Article
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Efficacy at g-protein-coupled receptors

Nature Reviews Drug Discovery volume 1, pages 103–110 (2002)Cite this article

Key Points

  • Historically, efficacy was defined as the property of a molecule that produced receptor activation and a subsequent physiological tissue response.

  • New technologies have revealed that receptor proteins have a wide range of behaviours, and that some ligands can influence these behaviours without inducing a physiological response.

  • Whereas current thermodynamic models link efficacy with G-protein activation, a more flexible model based on the idea that proteins adopt numerous conformations, and that some of these have physiological significance, uniformly describes how ligands can have a number of 'efficacies'.

  • In terms of this model, ligand binding produces a different set of conformations, and, as some of these produce receptor effects, they determine the various efficacies of that molecule.

  • The model is heuristic and useful as a conceptual tool, but cannot fit data due to the large number of parameters that cannot be estimated independently.

  • Examples are given of ligands that do not produce physiological G-protein mediated response, but do cause receptor phosphorylation, dimerization and internalization.

  • In view of the relationship between efficacy and affinity, these ideas suggest that molecules that have affinity for receptors but do not produce overt physiological response should be studied for other receptor-related activities that might be useful therapeutically.

Abstract

At present, the drug-discovery process centres on ligands that either block or produce physiological responses. However, there are therapeutic uses for ligands that do neither of these things, but which still affect receptors in other ways. This review discusses the intimate relationship between the affinity of a ligand for its receptor, and the probability that the binding of the ligand will produce some change in the receptor, resulting in efficacy. This, in turn, argues that ligands that have affinity should be tested more broadly, for a wider range of efficacies, to detect hidden therapeutic activities.

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Figure 1: Schematic diagram of a hypothetical G-protein-coupled receptor.
Figure 2: GPCR ensembles.
Figure 3: Detection of ligand binding through observation of constitutive receptor activity.

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Acknowledgements

T.K. would like to thank O. Onaran, University of Ankara, Turkey, for insightful discussions on mechanisms of efficacy.

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Authors and Affiliations

  1. GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, North Carolina, 27709, USA

    Terry Kenakin

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DATABASES

LocusLink

angiotensin II

angiotensin II receptor

bradykinin receptor

CCK receptor

CCR2

CCR5

cholecystokinin

dopamine D2 receptor

RAMPs

RANTES

somatostatin receptor

FURTHER INFORMATION

G proteins

G-protein-coupled receptors

Glossary

LINKAGE THEORY

Based on the first law of thermodynamics, linkage theory creates models of protein species that are connected, and which can interconvert either spontaneously or through interaction with other species, such as ligands and G proteins. The interconversion pathways between any species are of equal energy, so none are preferred.

PLEIOTROPIC RECEPTOR

A receptor that couples to more than one G protein. An example is the human calcitonin receptor, which couples to Gi, Gs and Gq proteins.

PLEIOTROPIC COUPLING

Literally meaning 'having mulitple phenotypic expressions', in this case, pleiotropic coupling refers to the ability of some receptors to activate more than one G protein and therefore stimulate multiple response pathways in cells.

ENSEMBLE THEORY

This usage refers to the study of proteins as collections of microconformations, some being energetically preferred over others. The interaction of these collections of conformations with ligands causes them to redistribute the relative conformations into a new ensemble.

PDZ DOMAIN

(PSD-95, Dlg and ZO-1/2). Protein–protein interaction domain that binds to carboxy-terminal polypeptides in particular.

SH2 DOMAIN

(Src-homology domain 2). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

SH3 DOMAIN

(Src-homology domain 3.) A protein sequence of ∼50 amino acids that recognizes and binds sequences that are rich in proline.

MACRO-AFFINITY

Although some ligands will bind preferentially to some receptor conformations over others, the weighted average affinity that a ligand has for a receptor ensemble is known as the 'macro-affinity' of the ligand for the receptor. It is the concentration of ligand that is bound to 50% of the receptors at any one instant.

TACHYPHYLLAXIS

The reduction in response during repeated receptor stimulation by an agonist; usually ascribed to the production of a desensitized state of the receptor.

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Kenakin, T. Efficacy at g-protein-coupled receptors. Nat Rev Drug Discov 1, 103–110 (2002). https://doi.org/10.1038/nrd722

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