GPCR, family 2, latrophilin (GPCR_2_latrophilin)
Type: Family

Latrophilins are a family of secretin-like GPCRs that can be subdividedinto 3 subtypes: LPH1, LPH2 and LPH3. LPH1 is a brain-specific calcium independent receptor of alpha-latrotoxin (LTX), a neurotoxin. It is the affinity of this form of the receptor for LTX that gives the family its name. LPH2 and LPH3, whilst sharing extensive sequence similarity to LPH1, do not bind LTX. LPH2 is distributed throughout most tissues, whereas LPH3 is also brain-specific . The endogenous ligand(s) for these receptors are at present unknown. Binding of LTX to LPH1 stimulates exocytosis and the subsequent release of large amounts of neurotransmitters from neuronal and endocrine cells. The latrophilins possess up to 7 sites of alternative splicing; the resulting number of possible splice variants leads to a highly variable family of proteins.

Structurally, these proteins have a seven-transmembrane region and a large extracellular N-terminal region which consists of several domains: a rhamnose binding lectin (RBL) domain, an olfactomedin-like (OLF) domain followed by a Serine/Threonine rich domain that is O-linked glycosylated, a hormone binding (HR) domain; and a GPCR Autoproteolysis INducing (GAIN) domain .

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The secretin-like GPCRs include secretin , calcitonin , parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide , all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.