GPCR monomers and oligomers: it takes all kinds

Accumulating evidence of G-protein-coupled receptor (GPCR) oligomerization on the one hand and perfect functionality of monomeric receptors on the other creates an impression of controversy. However, the GPCR superfamily is extremely diverse, both structurally and functionally. The life cycle of each receptor includes many stages: synthesis, quality control in the endoplasmic reticulum, maturation in the Golgi, delivery to the plasma membrane (where it can be in the inactive or active state, in complex with cognate G protein, G-protein-coupled receptor kinase or arrestin), endocytosis and subsequent sorting in endosomes. Different GPCR subtypes, and even the same receptor at different stages of its life cycle, most likely exist in different oligomerization states, from monomers to dimers and possibly higher-order oligomers. Accumulating evidence of G-protein-coupled receptor (GPCR) oligomerization on the one hand and perfect functionality of monomeric receptors on the other creates an impression of controversy. However, the GPCR superfamily is extremely diverse, both structurally and functionally. The life cycle of each receptor includes many stages: synthesis, quality control in the endoplasmic reticulum, maturation in the Golgi, delivery to the plasma membrane (where it can be in the inactive or active state, in complex with cognate G protein, G-protein-coupled receptor kinase or arrestin), endocytosis and subsequent sorting in endosomes. Different GPCR subtypes, and even the same receptor at different stages of its life cycle, most likely exist in different oligomerization states, from monomers to dimers and possibly higher-order oligomers. A family of four proteins in mammals that specifically bind active phosphorylated GPCRs, shut down ('arrest') G-protein-mediated signaling, promote receptor internalization by linking it to the clathrin coat and redirect the signaling to multiple G-protein-independent pathways. A large family of receptors (encoded by >800 genes in the human genome) that have in common a characteristic bundle of seven membrane-spanning α helices (heptahelical domain) with an extracellular N terminus and intracellular C terminus. GPCRs are sometimes called seven-transmembrane receptors (7TMRs) to acknowledge the fact that some members of this family do not couple to G proteins. According to the most widely used (although not the most comprehensive) classification system, GPCRs are divided into classes (also termed families or groups) A, B and C. The largest group of GPCRs, which are often called rhodopsin-like receptors. Small-molecule and peptide agonists of these receptors usually bind within the cavity in the heptahelical domain and/or to the extracellular loops between the helices (with the exception of a few glycoprotein hormone receptors carrying large hormone-binding domains on the extracellular N terminus). The lengths of the C terminus and third intracellular loop in class A are highly variable. Typical examples: rhodopsin, α- and β-adrenergic, muscarinic cholinergic, dopamine and odorant receptors. A small group of receptors with relatively large extracellular N-terminal hormone-binding domains. Typical examples: corticotropin-releasing factor receptor, parathyroid hormone receptor. A small group of receptors that have been unambiguously shown to function as dimers. The ligand-binding site in these receptors is localized in the extracellular N-terminal Venus flytrap domain. Typical examples: homodimeric metabotrophic glutamate and calcium-sensing receptors, heterodimeric GABAB and sweet and umami taste receptors. Guanyl nucleotide-binding proteins. Active GPCRs function as guanyl nucleotide exchange factors (GEFs) of heterotrimeric G proteins, promoting the exchange of GDP for GTP on their α subunit. G-protein-coupled receptor kinases specifically phosphorylate agonist-activated GPCR, initiating the shutoff of G-protein-mediated signaling (desensitization). Humans have seven GRK subtypes (some with a few splice variants).