Efficacy at g-protein-coupled receptors

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.