The activation mechanism of class‐C G‐protein coupled receptors

Summry— Class‐C G‐protein coupled receptors (GPCRs) represent a distant group among the large family of GPCRs. This class includes the receptors for the main neurotransmitters, glutamate and γ‐aminobutyric acid (GABA), and the receptors for Ca2+, some taste and pheromone molecules, as well as some orphan receptors. Like any other GPCRs, class‐C receptors possess a heptahelical domain (HD) involved in heterotrimeric G‐protein activation, but most of them also have a large extracellular domain (ECD) responsible for agonist recognition and binding. In addition, it is now well accepted that these receptors are dimers, either homo or heterodimers. This complex architecture raises a number of important questions. Here we will discuss our view of how agonist binding within the large ECD triggers the necessary change of conformation, or stabilize a specific conformation, of the heptahelical domain leading to G‐protein activation. How ligands acting within the heptahelical domain can change the properties of these complex macromolecules.