Molecular Basis of Inverse Agonism in a G Protein-Coupled Receptor

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 signaling1-5. 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. © 2005 Nature Publishing Group. All rights reserved.