Lysophospholipid GPCR Family Subtypes and Products

What Are Lysophospholipid Receptors?

Lysophospholipid receptors are a family of G protein-coupled receptors (GPCRs) comprised of two receptor subtypes: lysophosphatidic acid receptors (LPAs) and sphingosine-1-phosphate receptors (S1Ps). Lysophospholipid receptors are responsible for a variety of cell responses including angiogenesis, proliferation, migration, mitogenesis, and cytoskeleton changes. LPAs are a target for therapeutic applications in a wide range of disease areas, such as cardiovascular disease, inflammation, cancer, psychiatric disorders, and infertility. S1Ps already have a therapeutic application in the treatment of multiple sclerosis, and research is already being done to develop other S1P modulating drugs.

Lysophospholipid Receptor Information

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GPR87 is a recently discovered LPA receptor. It is highly expressed in neoplastic cells found in the cervical squamous, urinary bladder carcinomas, lung carcinomas, head and neck squamous cell carcinomas, and the placenta. GPR87 plays an important role in normal ovarian development as well as intracellular signal transduction. GPR87 has been linked to lung and ovarian cancer, as well as tumor cell survival. Current research strongly supports the role of GPR87 as a p53 regulator and its potential as a therapeutic target for the treatment of cancer.

The lipid growth factor lysophosphatidic acid (LPA) is responsible for cell signaling in diverse pathways including survival, proliferation, motility, and differentiation. LPA acts upon target cells by activating its cognate receptors, which belong to the G protein-coupled endothelial differentiation gene (EDG) family. Four mammalian cell surface LPA receptors have been identified so far: EDG-2 (LPA1), EDG-4 (LPA2), EDG-7 (LPA3) and LPA4 (GPR23/P2Y9). EDG-2 is the most widely expressed receptor, with high-level mRNAs in the colons, small intestine, placenta, brain and heart. Heterologous expression studies have shown that EDG-2 couples to both Gi/o and Gq to mediate PLC activation, inhibition of cAMP accumulation and activation of the MAPK pathway. EDG-2 deficient mice show phenotypic changes observed in psychiatric disease as well as impaired suckling behavior attributable to defective olfaction.

The lysophosphatidic acid receptor LPA2 or endothelial differentiation, G-protein coupled receptor 4(EDG-4) is expressed most abundantly in testes and peripheral blood leukocytes. It is reported to be a distinctive functional marker for ovarian carcinoma.

LPA and the structurally related lysophoslipid mediator sphingosine 1- phosphate (S1P) signal cells through a set of G protein-coupled receptors known as EDG receptors. Some EDG receptors (e.g., EDG1) are S1P receptors; others (e.g., EDG2) are LPA receptors. LPA3 receptor (EDG7) mediates responses preferentially to unsaturated LPA, whereas LPA2 receptor (EDG4) mediates responses to both saturated and unsaturated LPA.

Human LPA4 (also known as P2Y9 and GPR23) receptors are G protein-coupled receptors. The cDNA encodes a 370-amino-acid polypeptide. The LPA4 receptors are predominately expressed in ovary, and also present in kidney, skeletal muscle and other brain and peripheral tissues. In rat neuroblastoma cells overexpressing the receptors, LPA promotes neurite retraction and cell rounding indicating LPA4 may mediate morphological changes in neuronal cells. Studies in LPA4 knockout mice revealed a role of LPA4 in the negative control of cell migration.

LPA5 (GPR92) represents a putative orphan G protein coupled receptor with unknown functions. ESTs for LPA5 have been isolated from human normal brain, testis, and tonsil B-cell libraries and from a human blood cancer cell library (pre-B cell). LPA5 protein contains 372 amino acids and shared 36 to 40% sequence identity in the transmembrane regions with the G protein-coupled purinergic receptor P2Y5 (P2RY5), GPR23, and GPR17. Recently, functional characteristics of GPR92/LPA5 have been elucidated that demonstrate the receptor’s identity as an LPA receptor.

S1P1 (or EDG1) is a widely distributed G-protein-coupled receptor for sphingosine-1-phosphate (S1P), a blood-borne bioactive lipid. Stimulation of the S1P1 receptor triggers a Gi-linked pathway, leading to growth, survival, migration, and morphogenesis. Disruption of the S1P1 gene in mice results in embryonic lethality because of its key role within endothelial cells in regulating the coverage of blood vessels by vascular smooth muscle cells. S1P1 also mediates activation of Rac and functions as a typical chemotactic receptor.

EDG-5 (Endothelial Differentiation Gene) is a member of G protein coupled sphingosine-1-phosphate receptor family, which includes S1P1 (EDG-1), S1P2 (EDG-5/H218/AGR16), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG- 8/NRG-1). Sphingosine-1-phosphate (SPP) is a bioactive lipid produced from the metabolism of sphingomyelin. It is an important constituent of serum and regulates cell growth, survival, migration, differentiation and gene expression via its interaction with the S1P family of G-protein coupled receptors. EDG-5 couple to a variety of G proteins i.e. Gi, Gq, G12, and G13 to activate extracellular signal-regulated kinase and mobilize Ca2+ and activate Elk-1- and serum-response factor (SRF)-driven gene transcription. Recent data suggest that EDG-5 also regulates Rho/Rho kinase pathway to inhibit tumor cell migration

S1P3 (sphingosine 1-phosphate receptor 3) or EDG3 (endothelial differentiation G-protein coupled receptor 3) is a receptor for the lysosphingolipid sphingosine 1-phosphate, a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. EDG receptors mediate pro- angiogenic activities, such as endothelial cell proliferation, chemotaxis, and vessel morphogenesis. S1P3, along with S1P1, is required for directing the organization of endothelial cells into capillary networks.

S1P4 receptor or Endothelial Differentiation Gene-6 (EDG-6) is receptor for sphingosine-1-phosphate (S1P). S1P is a bioactive lipid produced from the metabolism of sphingomyelin. It is an important constituent of serum and regulates cell growth, survival, migration, differentiation and gene expression. Unlike other members of S1P receptor, which are widely expressed, S1P4 exhibits lymphoid tissue-specific expression. EDG-6 has been implicated in regulation of cell shape and motility.

S1P5 or EDG8 is a 400-amino acid 7 transmembrane protein that shares 42-49% amino acid identity with the human S1P receptors EDG1, EDG3, and EDG5. Northern blot analysis has shown widespread expression of EDG8 in rat tissues, with strongest expression in spleen and white matter tracts of the brain.

Lysophospholipid Cell Lines

Receptor FamilyReceptorSpeciesParentalStable Cell Lines Division-Arrested Cells Membranes
S1P1humanCHO-K1 Gαqi5CG1047-1DCG1047-1MCG1047-1
S1P2humanCHO-K1 Gαqi5CG1051-1DCG1051-1MCG1051-1
S1P3humanCHO-K1 Gαqi5CG1049-1DCG1049-1MCG1049-1
S1P3mouseCHO-K1 Gαqi5CGm1049-1DCGm1049-1MCGm1049-1
S1P3ratCHO-K1 Gαqi5CGr1049-1DCGr1049-1MCGr1049-1
S1P4humanCHO-K1 Gαqi5CG1052-1DCG1052-1MCG1052-1
S1P4mouseCHO-K1 Gαqi5CGm1052-1DCGm1052-1MCGm1052-1
S1P4ratCHO-K1 Gαqi5CGr1052-1DCGr1052-1MCGr1052-1
S1P5humanCHO-K1 Gαqi5CG1054-1DCG1054-1MCG1054-1