Functional Selectivity in GPCR Heterocomplexes

G protein-coupled receptors (GPCRs) can couple to more than one signaling pathway. Biophysical studies and pharmacological theory indicate that they exist in different active conformations that differ in their capacity to activate specific signaling pathways. Individual agonists stabilize particular active conformations and thereby can differ in their relative activation of different signaling pathways coupled to the same receptor, a phenomenon referred to as functional selectivity. Many pairs of GPCRs have been shown to interact and form heterocomplexes in vitro and in vivo. Recent studies implicate these complexes in the responses to some therapeutic drugs and drugs of abuse, and raise the possibility that they may be involved in mediating functional selectivity.