EDG-6 sphingosine 1-phosphate receptor (EDG6_rcpt)
Type: Family

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 rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. 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 .

Lysophospholipids (LPs), such as lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), have long been known to act as signalling molecules in addition to their roles as intermediates in membrane biosynthesis . They have roles in the regulation of cell growth, differentiation, apoptosis and development, and have been implicated in a wide range of pathophysiological conditions, including: blood clotting, corneal wounding, subarachinoid haemorrhage, inflammation and colitis . A number of G protein-coupled receptors bind members of the lysophopholipid family - these include: the cannabinoid receptors; platelet activating factor receptor; OGR1, an SPC receptor identified in ovarian cancer cell lines; PSP24, an orphan receptor that has been proposed to bind LPA; and at least 8 closely related receptors, the EDG family, that bind LPA and S1P .

S1P is released from activated platelets and is also produced by a number of other cell types in response to growth factors and cytokines . It is proposed to act both as an extracellular mediator and as an intracellular second messenger. The cellular effects of S1P include growth related effects, such as proliferation, differentiation, cell survival and apoptosis, and cytoskeletal effects, such as chemotaxis, aggregation, adhesion, morphological change and secretion. The molecule has been implicated in control of angiogenesis, inflammation, heart-rate and tumour progression, and may play an important role in a number of disease states, such as atherosclerosis, and breast and ovarian cancer . Recently, 5 G protein-coupled receptors have been identified that act as high affinity receptors for S1P, and also as low affinity receptors for the related lysophospholipid, SPC . EDG-1, EDG-3, EDG-5 and EDG-8 share a high degree of similarity, and are also referred to as lpB1, lpB3, lpB2 and lpB4, respectively. EDG-6 is referred to as lpC1, reflecting its more distant relationship to the other S1P receptors.

EDG-6 is expressed predominantly in lymphoid and haematopoietic tissues and in lung, a distribution that is quite restricted relative to other EDG family members . Binding of S1P to the receptor leads to activation of phospholipase C and MAP kinases in a pertussis toxin sensitive manner, through coupling to proteins of the Gi class. Whether EDG-6 can couple to any other G protein families is currently not known .