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J. Biol. Chem., Vol. 280, Issue 41, 34458-34464, October 14, 2005

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Prostaglandin I₂ Production and cAMP Accumulation in Response to Acidic Extracellular pH through OGR1 in Human Aortic Smooth Muscle Cells^*

Hideaki Tomura1, Ju-Qiang Wang, Mayumi Komachi, Alatangaole Damirin, Chihiro Mogi, Masayuki Tobo, Junko Kon, Norihiko Misawa, Koichi Sato, and Fumikazu Okajima

From the Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan and the Central Laboratories for Key Technology, Kirin Brewery Co., LTD, 1-13-5, Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan

Ovarian cancer G-protein-coupled receptor 1 (OGR1) and GPR4 have recently been identified as proton-sensing or extracellular pHresponsive G-protein-coupled receptors stimulating inositol phosphate production and cAMP accumulation, respectively. In the present study, we found that OGR1 and GPR4 mRNAs were expressed in human aortic smooth muscle cells (AoSMCs). Acidic extracellular pH induced inositol phosphate production, a transient increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i), and cAMP accumulation in these cells. When small interfering RNAs (siRNAs) targeted for OGR1 and GPR4 were transfected to the cells, the acidinduced inositol phosphate production and [Ca²⁺]_i increase were markedly inhibited by the OGR1 siRNA but not by the GPR4 siRNA. Unexpectedly, the acid-induced cAMP accumulation was also largely inhibited by OGR1 siRNA but only slightly by GPR4 siRNA. Acidic extracellular pH also stimulated prostaglandin I2 (PGI₂) production, which was again inhibited by OGR1 siRNA. The specific inhibitors for extracellular signal-regulated kinase kinase and cyclooxygenase attenuated the acid-induced PGI₂ production and cAMP accumulation without changes in the inositol phosphate production. A specific inhibitor of phospholipase C also inhibited the acid-induced cAMP accumulation. In conclusion, OGR1 is a major receptor involved in the extracellular acid-induced stimulation of PGI₂ production and cAMP accumulation in AoSMCs. The cAMP accumulation may occur through OGR1-mediated stimulation of the phospholipase C/cyclooxygenase/PGI₂ pathway.

Received for publication, May 13, 2005 , and in revised form, August 4, 2005.

^* This work was supported by grants-in-aid for scientific research from the Japan Society for the Promotion of Science, a grant of the 21^st Century COE Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and grants from The Nakatomi Foundation and The Uehara Memorial Foundation. 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.

¹ To whom correspondence should be addressed: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan. Tel.: 81-27-220-8851; Fax: 81-27-220-8895; E-mail: tomurah{at}showa.gunma-u.ac.jp.

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