Molecular Basis of Partial Agonism at the Neurotransmitter α2A-Adrenergic Receptor and Gi-protein Heterotrimer*

To characterize the mechanism by which heterotrimeric G-proteins interpret the signals coming from various neurotransmitters of diverse efficacies (agonists and partial agonists) acting on α2A-adrenergic receptors, we used a fluorescent resonance energy transfer-based approach to study the effects of these partial agonists on the activation process of both the α2A-adrenergic receptor and its cognate Gi-protein. We show that ligands of different efficacies switch the receptor into distinct conformational states, which in turn set the speed and extent of the Gi-protein signaling. Thus, in cells the efficacy by which a receptor responds to diverse ligands is caused by the ability of the G-protein to differentiate between distinct receptor conformations. The data provide a new key characteristic underlying the mechanism of partial agonism at G-protein-coupled receptors.