Alternative titles; symbols
HGNC Approved Gene Symbol: LPAR3
Cytogenetic location: 1p22.3 Genomic coordinates (GRCh38) : 1:84,811,602-84,893,206 (from NCBI)
The lysolipid mediator lysophosphatidic acid (LPA) is generated by phospholipase cleavage of membrane phospholipids from stimulated cells and platelets. LPA is present at micromolar concentrations in serum, and it elicits diverse biologic functions, including proliferation, platelet aggregation, smooth muscle contraction, inhibition of neuroblastoma cell differentiation, chemotaxis, and tumor cell invasion. LPA and the structurally related lysolipid 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, 601974) are S1P receptors; others (e.g., EDG2, 602282) are LPA receptors (summary by Chun et al., 2002). EDG7 mediates responses to unsaturated LPA (Bandoh et al., 1999).
Chun et al. (2002) proposed a nomenclature scheme for the LPA and S1P receptors that is consistent with the International Union of Pharmacology (IUP) guidelines. According to these guidelines, a receptor is to be named with the abbreviation of the natural agonist with the highest potency, followed by a subscripted arabic number. Thus they suggested that the designation EDG7 should be changed to LPA3.
By PCR amplification of Jurkat T-cell cDNA using degenerate primers corresponding to EDG2 and EDG4 (605110) sequences, Bandoh et al. (1999) isolated a cDNA encoding EDG7. Sequence analysis predicted that the 353-amino acid EDG7 protein shares approximately 54% and 49% amino acid identity with EDG2 and EDG4, respectively, and less than 40% identity with the S1P-specific receptors (e.g., EDG1). Northern blot analysis detected a 4.3-kb EDG7 transcript in heart, pancreas, prostate, and testis, with lower expression in lung, ovary, and some cancer cell lines. Western blot analysis showed that transfected cells express EDG7 as an approximately 35-kD protein.
By database analysis and 5-prime RACE of ovary and placenta cDNA, Fitzgerald et al. (2000) cloned an EDG7 splice variant that they designated HOFNH30. The deduced 354-amino acid receptor differs from EDG7 in 14 of the last 72 residues. Northern blot analysis detected HOFNH30 expression predominantly in placenta, with little expression in ovarian cancer and prostate, and no expression in testis, heart, and ovary. In contrast, EDG7 expression was detected in all tissues examined, with highest expression in prostate, ovarian cancer, testis, and normal ovary.
Contos and Chun (2001) cloned mouse Edg7, which they designated Lpa3. The deduced 354-amino acid protein has a 7-transmembrane structure. The mouse and human EDG7 transcripts share 84% nucleotide identity through the coding region. The mouse transcript contains 3 mRNA destabilization sequences in its 3-prime UTR, whereas the human transcript contains 8. Northern blot analysis detected highest Edg7 expression in mouse testis, kidney, and lung, with lower expression in intestine, heart, thymus, and stomach. RT-PCR detected expression in glial-like and teratocarcinoma cell lines. Contos and Chun (2001) noted that there are several polymorphisms in the human EDG7 gene that do not alter the encoded protein.
Functional analysis by Bandoh et al. (1999) demonstrated increased calcium mobilization in EDG7- and EDG4- but not EDG2-expressing insect cells. EDG7 mediated responses preferentially to unsaturated LPA, whereas EDG4 mediated responses to both saturated and unsaturated LPA. Cyclic AMP accumulation was increased in EDG7- and EDG4- but not EDG2-expressing cells in response to forskolin and LPA. Unlike EDG4-expressing mammalian cells, EDG7- and EDG2-expressing cells were not coupled to mitogen-activated protein kinase (MAPK) activation.
Fitzgerald et al. (2000) found that human HOFNH30 expressed in rat leukemia cells mobilized calcium in response to LPA and phosphatidic acid. LPA also induced phosphorylation of the MAPKs p42 (MAPK1; 176948) and p44 (MAPK3; 601795) in transfected cells.
Ye et al. (2005) reported that LPA3 has an important molecular influence on embryo implantation. Targeted deletion of Lpa3 in mice resulted in significantly reduced litter size, which could be attributed to delayed implantation and altered embryo spacing. These 2 events led to delayed embryonic development, hypertrophic placentas shared by multiple embryos, and embryonic death. An enzyme demonstrated to influence implantation, cyclooxygenase-2 (COX2; 600262), was downregulated in Lpa3-deficient uteri during preimplantation. Downregulation of COX2 led to reduced levels of prostaglandins E2 (PGE2; see 176804) and PGI2 (see 600022), which are critical for implantation. Exogenous administration of PGE2 or carbaprostacyclin (a stable analog of PGI2) into Lpa3-deficient female mice rescued delayed implantation but did not rescue defects in embryo spacing. Ye et al. (2005) concluded that their data identified LPA3 receptor-mediated signaling as having an influence on implantation, and further indicated linkage between LPA signaling and prostaglandin biosynthesis.
Contos and Chun (2001) determined that the EDG7 gene contains 3 exons. Exon 1 is noncoding. The mouse Edg7 gene has a similar organization.
By radiation hybrid analysis, Fitzgerald et al. (2000) mapped the LPAR3 gene to chromosome 1p31.1-p22.3.
By backcross analysis, Contos and Chun (2001) mapped the mouse Edg7 gene to a region on distal chromosome 3 that shares homology of synteny with human chromosome 1p32.1-p22.2.
Bandoh, K., Aoki, J., Hosono, H., Kobayashi, S., Kobayashi, T., Murakami-Murofushi, K., Tsujimoto, M., Arai, H., Inoue, K. Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid. J. Biol. Chem. 274: 27776-27785, 1999. [PubMed: 10488122] [Full Text: https://doi.org/10.1074/jbc.274.39.27776]
Chun, J., Goetzl, E. J., Hla, T., Igarashi, Y., Lynch, K. R., Moolenaar, W., Pyne, S., Tigyi, G. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharm. Rev. 54: 265-269, 2002. [PubMed: 12037142] [Full Text: https://doi.org/10.1124/pr.54.2.265]
Contos, J. J. A., Chun, J. The mouse lpA3/Edg7 lysophosphatidic acid receptor gene: genomic structure, chromosomal localization, and expression pattern. Gene 267: 243-253, 2001. Note: Erratum: Gene 272: 345 only, 2001. [PubMed: 11313151] [Full Text: https://doi.org/10.1016/s0378-1119(01)00410-3]
Fitzgerald, L. R., Dytko, G. M., Sarau, H. M., Mannan, I. J., Ellis, C., Lane, P. A., Tan, K. B., Murdock, P. R., Wilson, S., Bergsma, D. J., Ames, R. S., Foley, J. J., Campbell, D. A., McMillan, L., Evans, N., Elshourbagy, N. A., Minehart, H., Tsui, P. Identification of an EDG7 variant, HOFNH30, a G-protein-coupled receptor for lysophosphatidic acid. Biochem. Biophys. Res. Commun. 273: 805-810, 2000. [PubMed: 10891327] [Full Text: https://doi.org/10.1006/bbrc.2000.2943]
Ye, X., Hama, K., Contos, J. J. A., Anliker, B., Inoue, A., Skinner, M. K., Suzuki, H., Amano, T., Kennedy, G., Arai, H., Aoki, J., Chun, J. LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 435: 104-108, 2005. [PubMed: 15875025] [Full Text: https://doi.org/10.1038/nature03505]