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Minireview: GPCR and G Proteins: Drug Efficacy and Activation in Live Cells

Department of Pharmacology and Chemical Biology (J.-P.V., T.N.F.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Endocrine Unit (J.-P.V.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; The Institute of Pharmacology and Toxicology (M.B., V.O.N., M.J.L., C.H.), and Rudolf Virchow Center (S.E., M.J.L.), Deutsche Forschungsgemeinschaft-Research Center for Experimental Biomedicine, University of Würzburg D-97078, Würzburg, Germany; and Department of Pharmacology and Toxicology (N.L.), Medical College of Georgia, Augusta, Georgia 30809

Address all correspondence and requests for reprints to: Jean-Pierre Vilardaga, Ph. D., Department of Pharmacology and Chemical Biology, Thomas E. Starzl Biochemical Science Tower, E1357, 200 Lothrop Street, Pittsburgh, Pennsylvania 15261. E-mail: jpv{at}pitt.edu.

Many biochemical pathways are driven by G protein-coupled receptors, cell surface proteins that convert the binding of extracellular chemical, sensory, and mechanical stimuli into cellular signals. Their interaction with various ligands triggers receptor activation that typically couples to and activates heterotrimeric G proteins, which in turn control the propagation of secondary messenger molecules (e.g. cAMP) involved in critically important physiological processes (e.g. heart beat). Successful transfer of information from ligand binding events to intracellular signaling cascades involves a dynamic interplay between ligands, receptors, and G proteins. The development of Förster resonance energy transfer and bioluminescence resonance energy transfer-based methods has now permitted the kinetic analysis of initial steps involved in G protein-coupled receptor-mediated signaling in live cells and in systems as diverse as neurotransmitter and hormone signaling. The direct measurement of ligand efficacy at the level of the receptor by Förster resonance energy transfer is also now possible and allows intrinsic efficacies of clinical drugs to be linked with the effect of receptor polymorphisms.