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Gene Review

gpr45  -  G protein-coupled receptor 45

Xenopus laevis

Synonyms: LPA, PSP24, lpar-a, xpsp24
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Disease relevance of lpar-a

  • Overexpression of either gene in oocytes potentiated LPA-induced oscillatory chloride ion currents through a pertussis toxin-insensitive pathway [1].
  • Furthermore, retrovirus-mediated heterologous expression of xlp(A1)-1 or xlp(A1)-2 in B103 rat neuroblastoma cells that are unresponsive to LPA conferred LPA-induced cell rounding and adenylyl cyclase inhibition [1].
  • Like LPA, the L-serine-based lipid mobilizes calcium and inhibits activation of adenylyl cyclase in the human breast cancer cell line MDA MB231 [2].
  • Consistent with this receptor subtype selectivity, dioctylglycerol pyrophosphate inhibited cellular responses to LPA in NIH3T3 fibroblasts, HEY ovarian cancer cells, PC12 pheochromocytoma cells, and Xenopus laevis oocytes [3].
  • Understanding the mechanisms regulating LPA production, metabolism and function could lead to improved methods for early detection and to new targets for therapy in ovarian cancer [4].

High impact information on lpar-a

  • Previous work has shown that guidance cues trigger rapid changes in protein dynamics in retinal growth cones: netrin-1 stimulates both protein synthesis and degradation, while Sema3A elicits synthesis, and LPA induces degradation [5].
  • This suggests a common link between closure of gap junctions by v-src and other mitogens, such as EGF and lysophosphatidic acid (LPA) [6].
  • An antisense oligonucleotide derived from the first 5-11 predicted amino acids, selectively inhibited the expression of the endogenous high-affinity LPA receptors in Xenopus oocytes, whereas the same oligonucleotide did not affect the low-affinity LPA receptor [7].
  • Lysophosphatidic acid (1-acyl-2-lyso-snglycero-3-phosphate, LPA) is a multifunctional lipid mediator found in a variety of organisms that span the phylogenetic tree from humans to plants [7].
  • Although its physiological function is not clearly understood, LPA is a potent regulator of mammalian cell proliferation; it is one of the major mitogens found in blood serum [7].

Chemical compound and disease context of lpar-a


Biological context of lpar-a

  • This current, like other effects of LPA, is consistent with a plasma membrane receptor-mediated activation of G protein-linked signal transduction pathways [7].
  • We previously showed that lysophosphatidic acid (LPA) signaling controls the change in cortical actin density that occurs at different stages of the cell cycle [10].
  • These results suggest that the bulk of LPA produced through platelet activation results from the sequential cleavage of phospholipids to lysophospholipids by released phospholipases A1 and A2 and then to LPA by plasma lysophospholipase D [11].
  • These results indicate that XLP(A1)-1 and XLP(A1)-2 are functional Xenopus LPA receptors and demonstrate the evolutionary conservation of LPA signaling over a range of vertebrate phylogeny [1].
  • Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (Sph1P) production was examined in vitro under conditions that simulated blood clotting [11].

Anatomical context of lpar-a


Associations of lpar-a with chemical compounds

  • Oocytes expressing cRNA prepared from this clone showed no response to other lipid mediators including prostaglandins, leukotrienes, sphingosine 1-phosphate, sphingosylphosphorylcholine, and platelet-activating factor, suggesting that the receptor is highly selective for LPA [7].
  • 1) Platelet phospholipids were labeled using [32P]orthophosphate, and the production of [32P]Sph1P and LPA was examined [11].
  • Incubation of [(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl-(NBD)-labeled phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine with the supernatant fractions from thrombin-stimulated platelets yielded no LPA production [11].
  • We report now the agonist activity of a synthetic phospholipid in which the glycerol backbone of LPA is replaced by L-serine [2].
  • Ropivacaine inhibited LPA signaling in a stereoselective and noncompetitive manner, suggesting a protein interaction [16].

Analytical, diagnostic and therapeutic context of lpar-a

  • We now describe a method that utilizes one HPLC run to separate trace amounts of PA and LPA from large amounts of lipids found in cellular extracts [14].
  • In contrast, microinjection of the C3 coenzyme of botulinum toxin, which selectively ADP-ribosylates and inactivates Rho, inhibited LPA-stimulated, but not IGF-I-stimulated, deoxyglucose uptake [17].
  • In contrast, the amount of LPA-like factors generated 4 days after intrathecal injection of autologous blood was in the range of 1-10 microM LPA equivalents [9].
  • By use of a combination of HPLC, two-dimensional TLC, mass spectrometry, and the Xenopus oocyte bioassay, the LPA-like phospholipids LPA, cyclic PA, alkenyl-glycerophosphate (GP), lysophosphatidylserine, and phosphatidic acid were detected as physiological constituents of the fluids bathing the cornea [18].


  1. Two novel Xenopus homologs of mammalian LP(A1)/EDG-2 function as lysophosphatidic acid receptors in Xenopus oocytes and mammalian cells. Kimura, Y., Schmitt, A., Fukushima, N., Ishii, I., Kimura, H., Nebreda, A.R., Chun, J. J. Biol. Chem. (2001) [Pubmed]
  2. Characterization of a receptor subtype-selective lysophosphatidic acid mimetic. Hooks, S.B., Ragan, S.P., Hopper, D.W., Hönemann, C.W., Durieux, M.E., Macdonald, T.L., Lynch, K.R. Mol. Pharmacol. (1998) [Pubmed]
  3. Short-chain phosphatidates are subtype-selective antagonists of lysophosphatidic acid receptors. Fischer, D.J., Nusser, N., Virag, T., Yokoyama, K., Wang Da, n.u.l.l., Baker, D.L., Bautista, D., Parrill, A.L., Tigyi, G. Mol. Pharmacol. (2001) [Pubmed]
  4. Critical role of lysophospholipids in the pathophysiology, diagnosis, and management of ovarian cancer. Mills, G.B., Eder, A., Fang, X., Hasegawa, Y., Mao, M., Lu, Y., Tanyi, J., Tabassam, F.H., Wiener, J., Lapushin, R., Yu, S., Parrott, J.A., Compton, T., Tribley, W., Fishman, D., Stack, M.S., Gaudette, D., Jaffe, R., Furui, T., Aoki, J., Erickson, J.R. Cancer Treat. Res. (2002) [Pubmed]
  5. Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Campbell, D.S., Holt, C.E. Neuron (2003) [Pubmed]
  6. Dissection of the molecular basis of pp60(v-src) induced gating of connexin 43 gap junction channels. Zhou, L., Kasperek, E.M., Nicholson, B.J. J. Cell Biol. (1999) [Pubmed]
  7. Molecular cloning of a high-affinity receptor for the growth factor-like lipid mediator lysophosphatidic acid from Xenopus oocytes. Guo, Z., Liliom, K., Fischer, D.J., Bathurst, I.C., Tomei, L.D., Kiefer, M.C., Tigyi, G. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  8. G protein-activated K+ channels: a reporter for rapid activation of G proteins by lysophosphatidic acid in Xenopus oocytes. Itzhaki Van-Ham, I., Peleg, S., Dascal, N., Shapira, H., Oron, Y. FEBS Lett. (2004) [Pubmed]
  9. Lysophosphatidic acid alters cerebrovascular reactivity in piglets. Tigyi, G., Hong, L., Yakubu, M., Parfenova, H., Shibata, M., Leffler, C.W. Am. J. Physiol. (1995) [Pubmed]
  10. A novel G protein-coupled receptor, related to GPR4, is required for assembly of the cortical actin skeleton in early Xenopus embryos. Tao, Q., Lloyd, B., Lang, S., Houston, D., Zorn, A., Wylie, C. Development (2005) [Pubmed]
  11. Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine 1-phosphate generation in blood. Sano, T., Baker, D., Virag, T., Wada, A., Yatomi, Y., Kobayashi, T., Igarashi, Y., Tigyi, G. J. Biol. Chem. (2002) [Pubmed]
  12. Naturally occurring analogs of lysophosphatidic acid elicit different cellular responses through selective activation of multiple receptor subtypes. Fischer, D.J., Liliom, K., Guo, Z., Nusser, N., Virág, T., Murakami-Murofushi, K., Kobayashi, S., Erickson, J.R., Sun, G., Miller, D.D., Tigyi, G. Mol. Pharmacol. (1998) [Pubmed]
  13. Recombinant human G protein-coupled lysophosphatidic acid receptors mediate intracellular calcium mobilization. An, S., Bleu, T., Zheng, Y., Goetzl, E.J. Mol. Pharmacol. (1998) [Pubmed]
  14. Quantification of phosphatidic acid and lysophosphatidic acid by HPLC with evaporative light-scattering detection. Holland, W.L., Stauter, E.C., Stith, B.J. J. Lipid Res. (2003) [Pubmed]
  15. Lysophosphatidic acid as a regulator of endothelial/leukocyte interaction. Rizza, C., Leitinger, N., Yue, J., Fischer, D.J., Wang, D.A., Shih, P.T., Lee, H., Tigyi, G., Berliner, J.A. Lab. Invest. (1999) [Pubmed]
  16. Local anesthetic inhibition of G protein-coupled receptor signaling by interference with Galpha(q) protein function. Hollmann, M.W., Wieczorek, K.S., Berger, A., Durieux, M.E. Mol. Pharmacol. (2001) [Pubmed]
  17. Characterization of the intracellular signalling pathways that underlie growth-factor-stimulated glucose transport in Xenopus oocytes: evidence for ras- and rho-dependent pathways of phosphatidylinositol 3-kinase activation. Thomson, F.J., Jess, T.J., Moyes, C., Plevin, R., Gould, G.W. Biochem. J. (1997) [Pubmed]
  18. Growth factor-like phospholipids generated after corneal injury. Liliom, K., Guan, Z., Tseng, J.L., Desiderio, D.M., Tigyi, G., Watsky, M.A. Am. J. Physiol. (1998) [Pubmed]
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