Alternative titles; symbols
HGNC Approved Gene Symbol: LPAR1
Cytogenetic location: 9q31.3 Genomic coordinates (GRCh38): 9:110,873,263-111,038,998 (from NCBI)
The lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P; see 601974), are important extracellular signaling molecules. These lipid mediators are pleiotropic; among the most common cellular responses are mitogenesis, cell survival (antiapoptosis), inhibition of adenylyl cyclase, and calcium mobilization. Physiologic events associated with these mediators include platelet aggregation, vasopressor activity, wound healing, immune modulation, and angiogenesis. Many of the actions of LPA and S1P are mediated through a set of G protein-coupled receptors (GPCR), including EDG2 (summary by Chun et al., 2002).
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 EDG2 should be changed to LPA1.
An et al. (1997) cloned a cDNA homologous to that encoding sheep Edg2 protein from a human lung cDNA library. The clone exhibited the 7 transmembrane domains characteristic of G protein-coupled receptors. The predicted 364-amino acid protein is 96% identical to sheep and mouse Edg2 proteins and shares 60% identity with EDG1 (601974). By Northern blot analysis, An et al. (1997) detected 2 transcripts of 3 and 3.5 kb in most human tissues, with greatest abundance observed in brain.
The International Radiation Hybrid Mapping Consortium mapped the LPAR1 gene to chromosome 9 (SHGC-37372).
By interspecific backcross analysis, Contos and Chun (1998) mapped the Vzg1 gene to a proximal region of mouse chromosome 4.
The neurons of the mammalian cerebral cortex are generated from the ventricular zone (vz), a discrete proliferative region overlying the cerebral ventricles. Cortical neuroblasts display a stereotyped change in their morphology that is linked to their proliferation: during S phase the neuroblasts appear bipolar, and then 'round up' during G2 and undergo mitosis. Hecht et al. (1996) identified EDG2 as VZG1 (ventricular zone gene-1), a GPCR expressed in cortical neurogenic regions. Overexpression of VZG1 induced sustained, LPA-dependent cell rounding in mammalian cells and increased specific LPA binding in cell membranes. The authors concluded that VZG1 is a receptor for LPA, suggesting the operation of LPA signaling mechanisms in cortical neurogenesis.
Moolenaar et al. (1997) reviewed progress in the understanding of LPA action and signaling.
An et al. (1997) showed that in a serum response element reporter gene assay, HEK293 cells expressing human EDG2 protein showed an elevated response to LPA. Overexpression of human EDG2 protein in Chinese hamster ovary cells correlated with increases in specific binding of radiolabeled LPA. An et al. (1997) concluded that the human EDG2 protein functions as a cellular receptor for LPA.
Using the aequorin luminescence method to reduce nonspecific signals, An et al. (1998) determined that LPA induced increased calcium mobilization in cells expressing EDG2 or EDG4, probably through inositol triphosphate generated by phospholipase C activation. EDG4-mediated calcium mobilization utilizes both Gi (see GNAI1; 139310) and Gq (see GNAQ; 600998) proteins, whereas EDG2 utilizes pertussis toxin-sensitive Gi proteins only.
Mototani et al. (2008) analyzed SNPs in 44 GPCR candidate genes in 368 individuals with knee osteoarthritis (see 165720) and 323 controls and identified a SNP (rs10980705; -2820G-A) in the promoter region of the LPAR1 gene that showed significant association with disease (uncorrected p = 2.6 x 10(-5); odds ratio, 2.3). Transfection studies in a synovial cell line showed that the LPAR1 promoter with the A allele resulted in increased LPAR1 expression due to stronger binding affinity for AP1 (JUN; 165160).
Tager et al. (2008) found elevated levels of LPA in bronchoalveolar lavage (BAL) fluid from mice following lung injury in the bleomycin model of pulmonary fibrosis. In Edg2-null mice, both accumulation of fibroblasts and vascular leak induced by bleomycin challenge were markedly attenuated compared to wildtype mice, whereas leukocyte recruitment was preserved during the first week after injury. In BAL fluid from patients with idiopathic pulmonary fibrosis (see 178500), LPA levels were also increased, and inhibition of EDG2 markedly reduced fibroblast responses to the chemotactic activity of BAL fluid. Tager et al. (2008) concluded that the LPA-EDG2 pathway mediates both excessive accumulation of fibroblasts and persistent vascular leak that have been implicated in pulmonary fibrosis.
An, S., Bleu, T., Zheng, Y., Goetzl, E. J. Recombinant human G protein-coupled lysophosphatidic acid receptors mediate intracellular calcium mobilization. Molec. Pharm. 54: 881-888, 1998. [PubMed: 9804623] [Full Text: https://doi.org/10.1124/mol.54.5.881]
An, S., Dickens, M. A., Bleu, T., Hallmark, O. G., Goetzl, E. J. Molecular cloning of the human Edg2 protein and its identification as a functional cellular receptor for lysophosphatidic acid. Biochem. Biophys. Res. Commun. 231: 619-622, 1997. [PubMed: 9070858] [Full Text: https://doi.org/10.1006/bbrc.1997.6150]
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. Complete cDNA sequence, genomic structure, and chromosomal localization of the LPA receptor gene, Ip(A1)/vzg-1/Gpcr26. Genomics 51: 364-378, 1998. [PubMed: 9721207] [Full Text: https://doi.org/10.1006/geno.1998.5400]
Hecht, J. H., Weiner, J. A., Post, S. R., Chun, J. Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J. Cell Biol. 135: 1071-1083, 1996. [PubMed: 8922387] [Full Text: https://doi.org/10.1083/jcb.135.4.1071]
Moolenaar, W. H., Kranenburg, O., Postma, F. R., Zondag, G. C. M. Lysophosphatidic acid: G-protein signalling and cellular responses. Curr. Opin. Cell Biol. 9: 168-173, 1997. [PubMed: 9069262] [Full Text: https://doi.org/10.1016/s0955-0674(97)80059-2]
Mototani, H., Iida, A., Nakajima, M., Furuichi, T., Miyamoto, Y., Tsunoda, T., Sudo, A., Kotani, A., Uchida, A., Ozaki, K., Tanaka, Y., Nakamura, Y., Tanaka, T., Notoya, K., Ikegawa, S. A functional SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese. Hum. Molec. Genet. 17: 1790-1797, 2008. [PubMed: 18325907] [Full Text: https://doi.org/10.1093/hmg/ddn069]
Tager, A. M., LaCamera, P., Shea, B. S., Campanella, G. S., Selman, M., Zhao, Z., Polosukhin, V., Wain, J., Karimi-Shah, B. A., Kim, N. D., Hart, W. K., Pardo, A., Blackwell, T. S., Xu, Y., Chun, J., Luster, A. D. The lysophosphatidic acid receptor LPA(1) links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nature Med. 14: 45-54, 2008. [PubMed: 18066075] [Full Text: https://doi.org/10.1038/nm1685]