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 Gα subunit, leading to effector activation by both Gα–GTP and Gβγ. 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. 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 Gα subunit, leading to effector activation by both Gα–GTP and Gβγ. 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.