GPCRs family is a superfamily consisting of several subfamily, including Class A rhodopsin-like, Class B secretin-like, Class C metabotropic glutamate/pheromone, Class F frizzled (FZD), Taste receptors (TAS1R, TAS2R), Vomeronasal receptors (VN1R, VN2R) and 7TM orphan receptors. They are divided into 7 subfamily based on the type of stimuli that activates the GPCRs and sequence similarity. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices. Here, we introduce four main subfamilies of GPCRs: Class A rhodopsin-like, Class B secretin-like, Class C metabotropic glutamate/pheromone and Class F frizzled (FZD).
Class A rhodopsin-like GPCRs
Class A rhodopsin-like GPCRs are the largest subfamily of G protein-coupled receptors and make up about half of all GPCRs including hormones, neurotransmitters and light receptors. All of these proteins transduce extracellular signals through coupled guanine nucleotide-binding (G) proteins. Rhodopsin-like GPCRs have been divided into 21 subgroups based on a phylogenetic analysis according to HGNC database.
Class B secretin-like GPCRs
This subfamily of GPCRs is also known as Family B, the secretin-receptor family or family 2 of the GPCR. Many secretin-receptors are regulated by peptide hormones from the glucagon hormone family. Class B secretin-like GPCRs has been divided into the following 6 subgroups based on a phylogenetic analysis according to HGNC database, including Adhesion G protein-coupled receptors (ADGR), Calcitonin receptors (CALCR), Corticotropin-releasing factor receptors (CRHR), Glucagon receptor family, Vasoactive intestinal peptide receptor family and Parathyroid hormone receptors. There are 7 transmembrane helices in these receptors, the same as rhodopsin-like GPCRs. Class B secretin-like receptors activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway.
Class C metabotropic glutamate/pheromone GPCRs
The class C GPCRs is one of the subfamily in GPCRs, including the metabotropic glutamate receptors and several additional receptors. Class C metabotropic glutamate/pheromone has a large extracellular N-terminus which responds to the orthosteric (endogenous) ligand. The metabotropic glutamate receptors are different from the ionotropic glutamate receptors in function and pharmacology. They are coupled to G-proteins and stimulate the inositol phosphate/Ca2+ intracellular signaling pathway. There are 4 subgroups in Class C receptors, including Calcium-sensing receptors, Gamma-aminobutyric acid (GABA) B receptors (GABBR), Glutamate receptors metabotropic (GRM), Class C orphans.
Class F frizzled (FZD) GPCRs
Class F frizzled is a subfamily of GPCRs which contains the receptors in Wnt signaling pathway and other signaling pathways. It has been shown that the frizzled proteins play a key role in establishing and controlling planar cell polarity, embryonic development, cell proliferation, formation of neural synapses and many other processes in developing and adult organisms. In the developing wing, frizzled proteins transmit of an intracellular polarity signal for the proximal-distal and respond to the polarity signal for cells. The mutation of frizzled proteins can lead to some rare diseases, for example, mutations in the human frizzled-4 receptor have been related to familial exudative vitreoretinopathy. There are 11 genes in Class F frizzled receptors including FZD 1, FZD 2, FZD 3, FZD 4, FZD 5, FZD 6, FZD 7, FZD 8, FZD 9, FZD 10 and SMO.