Identification of Farnesyl Pyrophosphate and N-Arachidonylglycine as Endogenous Ligands for GPR92S

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 GPR9...

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Published in:	The Journal of biological chemistry Vol. 283; no. 30; pp. 21054 - 21064
Main Authors:	Oh, Da Young, Yoon, Jung Min, Moon, Mi Jin, Hwang, Jong-Ik, Choe, Han, Lee, Ju Yeon, Kim, Jae Il, Kim, Sunoh, Rhim, Hyewhon, O'Dell, David K., Walker, J. Michael, Na, Heung Sik, Lee, Min Goo, Kwon, Hyuk Bang, Kim, Kyungjin, Seong, Jae Young
Format:	Journal Article
Language:	English
Published:	American Society for Biochemistry and Molecular Biology 25-07-2008
Subjects:	Mechanisms of Signal Transduction
Online Access:	Get full text
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Summary:	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 Thr 97 , Gly 98 , Phe 101 , and Arg 267 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 Ca 2+ levels in cultured DRG neurons. These results suggest that FPP and NAG play a role in the sensory nervous system through activation of GPR92.
Bibliography:	The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4. 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. Passed away on January 5, 2008 in Bloomington, IN. This paper is dedicated to the memory of J. Michael Walker.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M708908200