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J. Biol. Chem., Vol. 283, Issue 30, 21054-21064, July 25, 2008

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Identification of Farnesyl Pyrophosphate and N-Arachidonylglycine as Endogenous Ligands for GPR92^*

Da Young Oh, Jung Min Yoon, Mi Jin Moon, Jong-Ik Hwang, Han Choe, Ju Yeon Lee^¶, Jae Il Kim^¶, Sunoh Kim^||, Hyewhon Rhim^**, David K. O'Dell, J. Michael Walker, Heung Sik Na, Min Goo Lee, Hyuk Bang Kwon^¶¶, Kyungjin Kim^||||, and Jae Young Seong¹

From the Laboratory of G Protein-Coupled Receptors and Department of Physiology, Korea University College of Medicine, Seoul 136-705, Korea, the Department of Physiology and Research Institute for Biomacromolecules, University of Ulsan College of Medicine, Seoul 138-736, Korea, the ^¶Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea, the ^||Bio-Safety Research Institute and College of Veterinary Medicine, Chonbuk National University, Jeonju 561-756, Korea, the ^**Life Sciences Division, Korea Institute of Science and Technology, Seoul 136-791, Korea, the Gill Center for Biomolecular Science and Program in Neuroscience, Indiana University, Bloomington, Indiana 47405, the ^¶¶School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Korea, and the ^||||School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea

A series of small compounds acting at the orphan G protein-coupled receptor GPR92 were screened using a signaling pathway-specific reporter assay system. Lipid-derived molecules including farnesyl pyrophosphate (FPP), N-arachidonylglycine (NAG), and lysophosphatidic acid were found to activate GPR92. FPP and lysophosphatidic acid were able to activate both G_q/11- and G_s-mediated signaling pathways, whereas NAG activated only the G_q/11-mediated signaling pathway. Computer-simulated modeling combined with site-directed mutagenesis of GPR92 indicated that Thr⁹⁷, Gly⁹⁸, Phe¹⁰¹, and Arg²⁶⁷ of GPR92 are responsible for the interaction of GPR92 with FPP and NAG. Reverse transcription-PCR analysis revealed that GPR92 mRNA is highly expressed in the dorsal root ganglia (DRG) but faint in other brain regions. Peripheral tissues including, spleen, stomach, small intestine, and kidney also expressed GPR92 mRNA. Immunohistochemical analysis revealed that GPR92 is largely co-localized with TRPV1, a nonspecific cation channel that responds to noxious heat, in mouse and human DRG. FPP and NAG increased intracellular Ca²⁺ levels in cultured DRG neurons. These results suggest that FPP and NAG play a role in the sensory nervous system through activation of GPR92.

Received for publication, October 29, 2007 , and in revised form, May 21, 2008.

This paper is dedicated to the memory of J. Michael Walker.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DA16825 and DA018224 from the National Institute on Drug Abuse (to J. M. W.). This work was also supported by Grants M103KV010005-08K2201-00510 (to J. Y. S.) and M103KV010007-07K2201-00710 (to H. R.) from the Brain Research Center of the 21st Century Frontier Research Program; the Linda and Jack Gill Center for Biomolecular Science, Indiana University, Bloomington, IN; and the Indiana Metabolomics and Cytomics Initiative (METACyt) Grant from Lilly Foundation Inc., Indianapolis, IN. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4.

Passed away on January 5, 2008 in Bloomington, IN.

¹ To whom correspondence and reprint requests should be addressed. Tel.: 82-2-920-6090; Fax: 82-2-921-4355; E-mail: jyseong{at}korea.ac.kr.

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