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Expression of Lysophosphatidic Acid Receptor in Rat Astrocytes: Mitogenic Effect and Expression of Neurotrophic Genes

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Abstract

Lysophosphatidic acid (LPA) is a phospholipid mediator with a variety of biological activities. It remains unknown, however, which cells in the brain express the LPA receptor. The present study was undertaken to identify cells in the rat brain expressing functional LPA receptors, and to explore biological roles of LPA in these cells. We found that the LPA receptor was most dominantly expressed in rat astrocytes, determined by LPA-induced Ca2+ imaging, and by Northern blot analyses. LPA induced a mitogenic response and expression of immediate early genes in astrocytes, through pertussis-toxin sensitive G-protein(s). LPA also stimulated the expression of various cytokine genes, including nerve growth factor, interleukin (IL)-1β, IL-3 and IL-6. Thus, astrocytes are the major target of LPA in the brain. We propose that LPA may play important roles in neuronal development, gliosis and wound-healing process in the brain.

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REFERENCES

  1. Moolenaar, W. H. 1995. Lysophosphatidic acid signalling. Curr. Opin. Cell. Biol. 7:203-210.

    Google Scholar 

  2. Moolenaar, W. H., Kranenburg, O., Postma, F. R., and Zondag, G. C. 1997. Lysophosphatidic acid: G-protein signalling and cellular responses. Curr. Opin. Cell. Biol. 9:168-173.

    Google Scholar 

  3. Das, A. K., and Hajra, A. K. 1989. Quantification, characterization and fatty acid composition of lysophosphatidic acid in different rat tissues. Lipids 24:329-333.

    Google Scholar 

  4. Tigyi, G., Hong, L., Yakubu, M., Parfenova, H., Shibata, M., Leffler, C. W. 1995. Lysophosphatidic acid alters cerebrovascular reactivity in piglets. Am. J. Physiol. 268:H2048-2055.

    Google Scholar 

  5. Thompson, F. J., Clark, M. A. 1994. Purification of a lysophosphatidic acid-hydrolysing lysophospholipase from rat brain. Biochem. J. 300:457-461.

    Google Scholar 

  6. Thomson, F. J., Clark, M. A. 1995. Purification of a phosphatidic-acid-hydrolysing phospholipase A2 from rat brain. Biochem. J. 306:305-309.

    Google Scholar 

  7. van der Bend, R. I., Brunner, J., Jalink, K., van C. E., Moolenaar, W. H., van B. W. 1992. Identification of a putative membrane receptor for the bioactive phospholipid, lysophosphatidic acid. EMBO J. 11:2495-2501.

    Google Scholar 

  8. Thomson, F. J., Perkins, L., Ahern, D., Clark, M. 1994. Identification and characterization of a lysophosphatidic acid receptor. Mol. Pharmacol. 45:718-723.

    Google Scholar 

  9. Shimizu, T., Wolfe, L. S. 1990. Arachidonic acid cascade and signal transduction. J. Neurochem. 55:1-15.

    Google Scholar 

  10. Bazan, N. G., Squinto, S. P., Braquet, P., Panetta, T., Marcheselli, V. L 1991. Platelet-activating factor and polyunsaturated fatty acids in cerebral ischemia or convulsions: intracellular PAF-binding sites and activation of a fos/jun/AP-1 transcriptional signaling system. Lipids 2:1236-1242.

    Google Scholar 

  11. Guo, Z., Liliom, K., Fischer, D. J., Bathurst, I. C., Tomei, L. D., Kiefer, M. C., Tigyi, G. 1996. Molecular cloning of a highaffinity receptor for the growth factor-like lipid mediator lysophosphatidic acid from Xenopus oocytes. Proc. Natl. Acad. Sci. USA 93:14367-14372.

    Google Scholar 

  12. Hecht, J. H., Weiner, J. A., Post, S. R., Chun, J. 1996. Ventricular zone gene-l (vzg-l) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J. Cell. Biol. 135:1071-1083.

    Google Scholar 

  13. An, S., Dickens, M. A., Bleu, T., Hallmark, O. G., and Goetzl EJ 1997. 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.

    Google Scholar 

  14. Bandoh, K., Aoki, J., Hosono, H., Kobayashi, S., Kobayashi, T., Murakami-Murofushi, K., Tsujimoto, M., Arai, H., and Inoue, K. 1999. Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid. J. Biol. Chem. 274:27776-27785.

    Google Scholar 

  15. Banker, G. A., and Cowan, W. M. 1977. Rat hippocampal neurons in dispersed cell culture. Brain Res. 126:397-342.

    Google Scholar 

  16. Mori, M., Aihara, M., Kume, K., Hamanoue, M., Kohsaka, S., and Shimizu, T. 1996. Predominant expression of platelet-activating factor receptor in the rat brain microglia. J. Neurosci. 16:3590-3600.

    Google Scholar 

  17. Chomczynski, P. 1992. One-hour downward alkaline capillary transfer for blotting of DNA and RNA. Anal. Biochem. 201:134-139.

    Google Scholar 

  18. van Straaten, F., Muller, R., Curran, T., and Van, B. C., Verma, I. M. 1983. Complete nucleotide sequence of a human c-onc gene: deduced amino acid sequence of the human c-fos protein. Proc. Natl. Acad. Sci. U S A 80:3183-3187.

    Google Scholar 

  19. Whittemore, S. R., Friedman, P. L., Larhammar, D., Persson, H., Gonzalez, C. M., and Holets, V. R. 1988. Rat beta-nerve growth factor sequence and site of synthesis in the adult hippocampus. J. Neurosci. Res. 20:403-410.

    Google Scholar 

  20. Dyer, D., Tigyi, G., and Miledi, R. 1992. The effect of active serum albumin on PC12 cells: II. Intracellular Ca2+ transients and their role in neurite retraction. Brain Res. Mol. Brain Res. 14:302-309.

    Google Scholar 

  21. Jalink, K., Eichholtz, T., Postma, F. R., van, C. E., and Moolenaar, W. H. 1993. Lysophosphatidic acid induces neuronal shape changes via a novel, receptor-mediated signaling pathway: similarity to thrombin action. Cell. Growth. Differ. 4:247-255.

    Google Scholar 

  22. van Corven, E., Groenink, A., Jalink, K., Eichholtz, T., and Moolenaar, W. H. 1989. Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins. Cell 59:45-54.

    Google Scholar 

  23. Fontana, A., Kristensen, F., Dubs; R., Gemsa, D., and Weber, E. 1982. Production of prostaglandin E and an interleukin-1 like factor by cultured astrocytes and C6 glioma cells. J. Immunol. 129:2413-2419.

    Google Scholar 

  24. Frei, K., Malipiero, U. V., Leist, T. P., Zinkernagel, R. M., Schwab, M. E., and Fontana, A. 1989. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur. J. Immunol. 19:689-694.

    Google Scholar 

  25. Frei, K., Bodmer, S., Schwerdel, C., and Fontana, A. 1985. Astrocytes of the brain synthesize interleukin 3-like factors. J. Immunol. 135:4044-4047.

    Google Scholar 

  26. Hildebrandt, J. P., and Hildebrandt, P. 1997. Lysophosphatidic acid depletes intracellular calcium stores different from those mediating capacitative calcium entry in C6 rat glioma cells. Glia 19:67-73.

    Google Scholar 

  27. Ashkenazi, A., Ramachandran, J., and Capon, D. J. 1989. Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes. Nature 340:146-150.

    Google Scholar 

  28. Levin, E. R., Frank, H. J., and Pedram, A. 1992. Endothelin receptors on cultured fetal rat diencephalic glia. J. Neurochem. 58:659-666.

    Google Scholar 

  29. Ciccarelli, R., Di, I. P., Ballerini, P., Ambrosini, G., Giuliani, P., Tiboni, G. M., and Caciagli, F. 1994. Effects of exogenous ATP and related analogues on the proliferation rate of dissociated primary cultures of rat astrocytes. J. Neurosci. Res. 39:556-566.

    Google Scholar 

  30. Grabham, P., and Cunningham, D. D. 1995. Thrombin receptor activation stimulates astrocyte proliferation and reversal of stellation by distinct pathways: involvement of tyrosine phosphorylation. J. Neurochem. 64:583-591.

    Google Scholar 

  31. Jalink, K., Hordijk, P. L., and Moolenaar, W. H. 1994. Growth factor-like effects of lysophosphatidic acid, a novel lipid mediator. Biochim. Biophys. Acta 1198:185-196.

    Google Scholar 

  32. Banker, G. A. 1980. Trophic interactions between astroglial cells and hippocampal neurons in culture. Science 209:809-810.

    Google Scholar 

  33. Hama, T., Miyamoto, M., Tsukui, H., Nishio, C., and Hatanaka, H. 1989. Interleukin-6 as a neurotrophic factor for promoting the survival of cultured basal forebrain cholinergic neurons from postnatal rats. Neurosci. Lett. 104:340-344.

    Google Scholar 

  34. Kamegai, M., Niijima, K., Kunishita, T., Nishizawa, M., Ogawa, M., Araki, M., Ueki, A., Konishi, Y., and Tabira, T. 1990. Interleukin 3 as a trophic factor for central cholinergic neurons in vitro and in vivo. Neuron 4:429-436.

    Google Scholar 

  35. Liliom, K., Guan, Z., Tseng, J. L., Desiderio, D. M., Tigyi, G., and Watsky, M. A. 1998. Growth factor-like phospholipids generated after corneal injury. Am. J. Physiol. 274:C1065-1074.

    Google Scholar 

  36. Reiser, C. O., Lanz, T., Hofmann, F., Hofer, G., Pupprecht, H. D., and Goppelt-Struebe M 1998. Lysophospatidic acid-mediated signal-transduction pathways involved in the induction of the early-response genes prostaglandin G/H synthase-2 and Erg-1: a critical role for the mitogen-activated protein kinase p38 and for Rho proteins. Biochem. J. 330 (3):1107-1114.

    Google Scholar 

  37. Olson, J. E., Fleischhacker, D., Murray, W. B., and Holtzman, D. 1990. Control of astrocyte volume by intracellular and extracellular Ca2+. Glia 3:405-412.

    Google Scholar 

  38. Tigyi, G., and Miledi, R. 1992. Lysophosphatidates bound to serum albumin activate membrane currents in Xenopus oocytes and neurite retraction in PC12 pheochromocytoma cells. J. Biol. Chem. 267:21360-21367.

    Google Scholar 

  39. Jalink, K., van C. E., Hengeveld, T., Morii, N., Narumiya, S., and Moolenaar, W.H. 1994. Inhibition of lysophosphatidateand thrombin-induced neurite retraction and neuronal cell rounding by ADP ribosylation of the small GTP-binding protein Rho. J. Cell. Biol. 126:801-810.

    Google Scholar 

  40. Remakers, G. J. A., and Moolenaar WH 1995. Actions of lysophosphatidic acid implicate the small GTP-binding protein Rho as a central regulator of astrocyte morphology. Soc. Neurosci. Abstr. 21:304.

    Google Scholar 

  41. Manning, T. J. Jr., Rosenfeld, S. S., and Sontheimer, H. 1998. Lysophosphatidic acid stimulates actomyosin contraction in astrocytes. J. Neurosci. Res. 53(3):343-352.

    Google Scholar 

  42. Wenzel, J., Lammert, G., Meyer, U., and Krug, M. 1991. The influence of long-term potentiation on the spatial relationship between astrocyte processes and potentiated synapses in the dentate gyrus neuropil of rat brain. Brain Res. 560:122-131.

    Google Scholar 

  43. Shibuki, K., Gomi, H., Chen, L., Bao, S., Kim, J. J., Wakatsuki, H., Fujisaki, T., Fujimoto, K., Katoh, A., Ikeda, T., Chen, C., Thompson, R. F., and Itohara, S. 1996. Deficient cerebellar long-term depression, impaired eyeblink conditioning, and normal motor coordination in GFAP mutant mice. Neuron 16:587-599.

    Google Scholar 

  44. Chun, J. 1999. Lysophospholipid receptors: implications for neural signaling. Crit. Rev. Neurobiol. 13(2):151-168.

    Google Scholar 

  45. Chun, J., Contos, J. J., and Munroe, D. 1999. A growing family of receptor genes for lysophosphatidic acid (LPA) and other lysophospholipids (LPs). Cell. Biochem. Biophys. 30:213-242.

    Google Scholar 

  46. Keller, J. N., Steiner, M. R., Mattson, M. P., and Steiner, S. M. 1996. Lysophosphatidic acid decreases glutamate and glucose uptake by astrocytes. J. Neurochem. 67:2300-2305.

    Google Scholar 

  47. Holtzberg, F. W., Steiner, M. R., Keller, J. N., Mark, R. J., Mattson, M. P., and Steiner, S. M. 1998. Lysophosphatidic acid induces necrosis and apoptosis in hippocampal neurons. J. Neurochem. 70(1):66-76.

    Google Scholar 

  48. Bavbek, M., Nietgen, G. W., Bogaev, C., Fineman, M. B., Polin, R., Chen, Z. F., Lee, K. S., Kassell, N. F., Durieux, M. E. 1996. Increased lysophosphatidate levels in CSF after subarachnoid hemorrhage. Soc. Neurosci. Abstr. 22:1566.

    Google Scholar 

  49. Schulze, C., Smales, C., Rubin, L. L., and Staddon, J. M. 1997. Lysophosphatidic acid increases tight junction permeability in cultured brain endothelial cells. J. Neurochem. 68:991-1000.

    Google Scholar 

  50. Weiner, J. A., Hecht, J. H., Chun, J. 1998. Lysophosphatidic acid receptor gene vzg-1/1pA1/edg-2 is expressed by mature oligodendrocytes during myelination in the postnatal murine brain. J. Comp. Neurol. 398(4):587-598.

    Google Scholar 

  51. Weiner, J. A., Chun, J. 1999. Schwann cell survival mediated by the signaling phospholipid lysophosphatidic acid. Proc. Natl. Acad. Sci. USA 96:5233-5238.

    Google Scholar 

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Authors and Affiliations

  1. Division of Neurosurgery, Institute of Neurological Sciences, Tottori University School of Medicine, Yonago, 683, Japan

    Sadaharu Tabuchi

  2. Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, 113, Japan

    Sadaharu Tabuchi, Kazuhiko Kume & Makoto Aihara

  3. Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, 113, Japan

    Takao Shimizu

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Tabuchi, S., Kume, K., Aihara, M. et al. Expression of Lysophosphatidic Acid Receptor in Rat Astrocytes: Mitogenic Effect and Expression of Neurotrophic Genes. Neurochem Res 25, 573–582 (2000). https://doi.org/10.1023/A:1007542532395

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