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Originally published In Press as doi:10.1074/jbc.M302648200 on April 30, 2003

J. Biol. Chem., Vol. 278, Issue 28, 25600-25606, July 11, 2003
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Identification of p2y9/GPR23 as a Novel G Protein-coupled Receptor for Lysophosphatidic Acid, Structurally Distant from the Edg Family*

Kyoko Noguchi, Satoshi Ishii {ddagger} and Takao Shimizu

From the Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Lysophosphatidic acid (LPA) is a bioactive lipid mediator with diverse physiological and pathological actions on many types of cells. LPA has been widely considered to elicit its biological functions through three types of G protein-coupled receptors, Edg-2 (endothelial cell differentiation gene-2)/LPA1/vzg-1 (ventricular zone gene-1), Edg-4/LPA2, and Edg-7/LPA3. We identified an orphan G protein-coupled receptor, p2y9/GPR23, as the fourth LPA receptor (LPA4). Membrane fractions of RH7777 cells transiently expressing p2y9/GPR23 displayed a specific binding for 1-oleoyl-LPA with a Kd value of around 45 nM. Competition binding and reporter gene assays showed that p2y9/GPR23 preferred structural analogs of LPA with a rank order of 1-oleoyl- > 1-stearoyl- > 1-palmitoyl- > 1-myristoyl- > 1-alkyl- > 1-alkenyl-LPA. In Chinese hamster ovary cells expressing p2y9/GPR23, 1-oleoyl-LPA induced an increase in intracellular Ca2+ concentration and stimulated adenylyl cyclase activity. Quantitative real-time PCR demonstrated that mRNA of p2y9/GPR23 was significantly abundant in ovary compared with other tissues. Interestingly, p2y9/GPR23 shares only 20–24% amino acid identities with Edg-2/LPA1, Edg-4/LPA2, and Edg-7/LPA3, and phylogenetic analysis also shows that p2y9/GPR23 is far distant from the Edg family. These facts suggest that p2y9/GPR23 has evolved from different ancestor sequences from the Edg family.

Received for publication, March 14, 2003 , and in revised form, April 28, 2003.

* This work was supported by grants-in-aid from the Ministry of Education, Science, Culture, Sports and Technology of Japan (to T. S. and S. I.), grants-in-aid for Comprehensive Research on Aging and Health, and Research on Allergic Disease and Immunology from the Ministry of Health, Labour, and Welfare, Japan, and grants from the Yamanouchi Foundation for Research on Metabolic Disorders, the Kanae Foundation for Life and Socio-medical Science, and the Uehara Memorial Foundation (to S. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} To whom correspondence should be addressed. Tel.: 81-3-5802-2925; Fax: 81-3-3813-8732; E-mail: mame{at}m.u-tokyo.ac.jp.


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K. Itagaki, K. B. Kannan, and C. J. Hauser
Lysophosphatidic acid triggers calcium entry through a non-store-operated pathway in human neutrophils
J. Leukoc. Biol., February 1, 2005; 77(2): 181 - 189.
[Abstract] [Full Text] [PDF]

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S. Bagga, K. S. Price, D. A. Lin, D. S. Friend, K. F. Austen, and J. A. Boyce
Lysophosphatidic acid accelerates the development of human mast cells
Blood, December 15, 2004; 104(13): 4080 - 4087.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
N. Murakami, T. Yokomizo, T. Okuno, and T. Shimizu
G2A Is a Proton-sensing G-protein-coupled Receptor Antagonized by Lysophosphatidylcholine
J. Biol. Chem., October 8, 2004; 279(41): 42484 - 42491.
[Abstract] [Full Text] [PDF]

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R. Cummings, Y. Zhao, D. Jacoby, E. W. Spannhake, M. Ohba, J. G. N. Garcia, T. Watkins, D. He, B. Saatian, and V. Natarajan
Protein Kinase C{delta} Mediates Lysophosphatidic Acid-induced NF-{kappa}B Activation and Interleukin-8 Secretion in Human Bronchial Epithelial Cells
J. Biol. Chem., September 24, 2004; 279(39): 41085 - 41094.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
B. Anliker and J. Chun
Lysophospholipid G Protein-coupled Receptors
J. Biol. Chem., May 14, 2004; 279(20): 20555 - 20558.
[Abstract] [Full Text] [PDF]

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K. Hama, J. Aoki, M. Fukaya, Y. Kishi, T. Sakai, R. Suzuki, H. Ohta, T. Yamori, M. Watanabe, J. Chun, et al.
Lysophosphatidic Acid and Autotaxin Stimulate Cell Motility of Neoplastic and Non-neoplastic Cells through LPA1
J. Biol. Chem., April 23, 2004; 279(17): 17634 - 17639.
[Abstract] [Full Text] [PDF]

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C. Zhang, D. L. Baker, S. Yasuda, N. Makarova, L. Balazs, L. R. Johnson, G. K. Marathe, T. M. McIntyre, Y. Xu, G. D. Prestwich, et al.
Lysophosphatidic Acid Induces Neointima Formation Through PPAR{gamma} Activation
J. Exp. Med., March 15, 2004; 199(6): 763 - 774.
[Abstract] [Full Text] [PDF]

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J. Xu, Y.-J. Lai, W.-C. Lin, and F.-T. Lin
TRIP6 Enhances Lysophosphatidic Acid-induced Cell Migration by Interacting with the Lysophosphatidic Acid 2 Receptor
J. Biol. Chem., March 12, 2004; 279(11): 10459 - 10468.
[Abstract] [Full Text] [PDF]

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 J. Lipid Res.Home page
D.-S. Im
Discovery of new G protein-coupled receptors for lipid mediators
J. Lipid Res., March 1, 2004; 45(3): 410 - 418.
[Abstract] [Full Text] [PDF]

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T. Yamada, K. Sato, M. Komachi, E. Malchinkhuu, M. Tobo, T. Kimura, A. Kuwabara, Y. Yanagita, T. Ikeya, Y. Tanahashi, et al.
Lysophosphatidic Acid (LPA) in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells through LPA1
J. Biol. Chem., February 20, 2004; 279(8): 6595 - 6605.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
H. Ohta, K. Sato, N. Murata, A. Damirin, E. Malchinkhuu, J. Kon, T. Kimura, M. Tobo, Y. Yamazaki, T. Watanabe, et al.
Ki16425, a Subtype-Selective Antagonist for EDG-Family Lysophosphatidic Acid Receptors
Mol. Pharmacol., October 1, 2003; 64(4): 994 - 1005.
[Abstract] [Full Text] [PDF]


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