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J. Biol. Chem., Vol. 279, Issue 44, 45626-45633, October 29, 2004

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TDAG8 Is a Proton-sensing and Psychosine-sensitive G-protein-coupled Receptor^*

Ju-Qiang Wang, Junko Kon, Chihiro Mogi, Masayuki Tobo, Alatangaole Damirin, Koichi Sato, Mayumi Komachi, Enkhzol Malchinkhuu, Naoya Murata, Takao Kimura, Atsushi Kuwabara, Kaori Wakamatsu, Hideki Koizumi¶, Toshimitsu Uede||, Gozoh Tsujimoto**, Hitoshi Kurose, Takashi Sato, Akihiro Harada, Norihiko Misawa¶, Hideaki Tomura, and Fumikazu Okajima¶¶

From the Laboratory of Signal Transduction and Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Department of Biochemical and Chemical Engineering, Faculty of Engineering, Gunma University, Kiryu 376-8515, ^¶Central Laboratories for Key Technology, Kirin Brewery Co., Ltd., 1-13-5, Fukuura, Kanazawa-ku, Yokohama 236-0004, ^||Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, Hokkaido 060-8638, ^**Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, and Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

T cell death-associated gene 8 (TDAG8) has been reported to be a receptor for psychosine. Ovarian cancer G-protein-coupled receptor 1 (OGR1) and GPR4, G-protein-coupled receptors (GPCRs) closely related to TDAG8, however, have recently been identified as proton-sensing or extracellular pH-responsive GPCRs that stimulate inositol phosphate and cAMP production, respectively. In the present study, we examined whether TDAG8 senses extracellular pH change. In the several cell types that were transfected with TDAG8 cDNA, cAMP was markedly accumulated in response to neutral to acidic extracellular pH, with a peak response at approximately pH 7.0–6.5. The pH effect was inhibited by copper ions and was reduced or lost in cells expressing mutated TDAG8 in which histidine residues were changed to phenylalanine. In the membrane fractions prepared from TDAG8-transfected cells, guanosine 5'-O-(3-thiotriphosphate) binding activity and adenylyl cyclase activity were remarkably stimulated in response to neutral and acidic pH. The concentration-dependent effect of extracellular protons on cAMP accumulation was shifted to the right in the presence of psychosine. The inhibitory psychosine effect was also observed for pH-dependent actions in OGR1- and GPR4-expressing cells but not for prostaglandin E₂- and sphingosine 1-phosphate-induced actions in any pH in native and sphingosine 1-phosphate receptor-expressing cells. Glucosylsphingosine and sphingosylphosphorylcholine similarly inhibited the pH-dependent action, although to a lesser extent. Psychosine-sensitive and pH-dependent cAMP accumulation was also observed in mouse thymocytes. We concluded that TDAG8 is one of the proton-sensing GPCRs coupling to adenylyl cyclase and psychosine, and its related lysosphingolipids behave as if they were antagonists against protein-sensing receptors, including TDAG8, GPR4, and OGR1.

Received for publication, June 22, 2004 , and in revised form, August 16, 2004.

^* This work was supported by grants-in-aid for scientific research from the Japan Society for the Promotion of Science, a research grant from O-No Medical Research Foundation, and the Japan-Korea Basic Scientific Cooperation Program. 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.

^¶¶ To whom correspondence should be addressed. Tel.: 81-27-220-8850; Fax: 81-27-220-8895; E-mail: fokajima{at}showa.gunma-u.ac.jp.

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