Evolution, Structure, and Activation Mechanism of Family 3/C G-protein-coupled Receptors

G-protein-coupled receptors (GPCRs) represent one of the largest gene families in the animal genome. These receptors can be classified into several groups based on the sequence similarity of their common heptahelical domain. The family 3 (or C) GPCRs are receptors for the main neurotransmitters glutamate and gamma-aminobutyric acid, for Ca(2+), for sweet and amino acid taste compounds, and for some pheromone molecules, as well as for odorants in fish. Although none of these family 3 receptors have been found in plants, members have been identified in ancient organisms, such as slime molds (Dictyostelium) and sponges. Like any other GPCRs, family 3 receptors possess a transmembrane heptahelical domain responsible for G-protein activation. However, most of these identified receptors also possess a large extracellular domain that is responsible for ligand recognition, is structurally similar to bacterial periplasmic proteins involved in the transport of small molecules, and is called a Venus Flytrap module. The recent resolution of the structure of this binding domain in one of these receptors, the metabotropic glutamate 1 receptor, together with the recent demonstration that these receptors are dimers, revealed a unique mechanism of activation for these GPCRs. Such data open new possibilities in the development of drugs aimed at modulating these receptors, and raise a number of interesting questions on the activation mechanism of the other GPCRs.