Family

Lysophosphatidic acid receptor EDG-2 (IPR002277)

Short name: LPA_rcpt_EDG2

Family relationships

Description

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 [PMID: 12679517]. 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 [PMID: 8170923]. 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) [PMID: 8170923, PMID: 8081729, PMID: 15914470, PMID: 18948278, PMID: 16753280]. 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 [PMID: 12679517]. 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 [PMID: 23020293].

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 [PMID: 2111655, PMID: 2830256, PMID: 8386361].

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 [PMID: 11264467]. 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 [PMID: 10603487]. 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 [PMID: 11264467].

LPA is found in all cell types in small quantities (associated with membrane biosynthesis) but is produced in significant quantities by some cellular sources, accounting for the levels of LPA in serum. LPA is also found in elevated levels in ovarian cancer ascites, and acts to stimulate proliferation and promote survival of the cancer cells [PMID: 11093753]. The effects of LPA on the proliferation and morphology of a number of other cell types have been well documented [PMID: 11264467, PMID: 11093753]. However, identification of the mechanisms by which these effects are accomplished has been complicated by a number of factors, such as: a lack of antagonists, difficulty in ligand-binding experiments and the responsiveness of many cell types to LPA [PMID: 11093753]. The G protein-coupled receptors EDG-2, EDG-4 and EDG-7 have now been identified as high affinity receptors for LPA. It has been suggested that these receptors should now be referred to as lpA1, lpA2 and lpA3 respectively [PMID: 11264467, PMID: 10603487].

EDG-2 was originally identified as a gene involved in neuron production from embryonic cerebral cortex [PMID: 11264467]. EDG-2 is widely distributed, with highest levels in the brain (in which expression correlates with development of oligodendrocytes and Schwann cells) [PMID: 11264467]. In the periphery, EDG-2 is found in many tissues, including the heart, kidney, testis, spleen and muscle in both humans and mouse [PMID: 11093753]. The receptor is also expressed in a number of cancers [PMID: 11264467]. Upon binding of LPA, EDG-2 couples to G proteins of the Gi, Gq and G12/13 classes, to mediate a range of effects including: inhibition of adenylyl cyclase; activation of phospholipase C, serum response element and MAP kinases; and actomyosin stimulation. These processes lead to cell rounding and proliferation [PMID: 11093753].

GO terms

Biological Process

GO:0007186 G-protein coupled receptor signaling pathway

Molecular Function

GO:0070915 lysophosphatidic acid receptor activity

Cellular Component

GO:0016021 integral component of membrane

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
PRINTS