Modulating G-protein-coupled receptors: from traditional pharmacology to allosterics

Signal transduction is the means by which cells respond to variations in their environment. G-protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors, accounting for > 1% of the human genome. GPCRs respond to a wide variety of extracellular signals, including peptides, ions, amino acids, hormones, growth factors, light and odorant molecules. The receptors couple with heterotrimeric G proteins to transduce their signal across the membrane and into the cell. This coupling promotes the exchange of GDP for GTP on the G alpha subunit, leading to effector activation by both G alpha-GTP and G beta gamma. Functional selectivity, whereby conformational changes in GPCRs induced by agonist binding lead to unique conformations that can differentially modulate the G protein coupling process, was first proposed over a decade ago. The implications are far reaching in pharmacology, as it means that a GPCR could have a different pharmacological profile depending on which G protein is activated and that the same GPCR could have different roles depending on the activating molecule as well as the G proteins present in the local environment.