J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M700513-JLR200 on January 3, 2008

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Journal of Lipid Research, Vol. 49, 797-803, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Elucidation of signaling and functional activities of an orphan GPCR, GPR81

Hongfei Ge*, Jennifer Weiszmann*, Jeff D. Reagan*, Jamila Gupte*, Helene Baribault*, Tibor Gyuris{dagger}, Jin-Long Chen*, Hui Tian* and Yang Li1,*

* Amgen, Inc., South San Francisco, CA 94080
{dagger} Amgen, Inc., Thousand Oaks, CA 91320

Published, JLR Papers in Press, January 3, 2008.

1 To whom correspondence should be addressed. e-mail: yangl{at}amgen.com

GPR81 is an orphan G protein-coupled receptor (GPCR) that has a high degree of homology to the nicotinic acid receptor GPR109A. GPR81 expression is highly enriched and specific in adipocytes. However, the function and signaling properties of GPR81 are unknown because of the lack of natural or synthetic ligands. Using chimeric G proteins that convert Gi-coupled receptors to Gq-mediated inositol phosphate (IP) accumulation, we show that GPR81 can constitutively increase IP accumulation in HEK293 cells and suggest that GPR81 couples to the Gi signaling pathway. We also constructed a chimeric receptor that expresses the extracellular domains of cysteinyl leukotriene 2 receptor (CysLT2R) and the intracellular domains of GPR81. We show that the CysLT2R ligand, leukotriene D4 (LTD4), is able to activate this chimeric receptor through activation of the Gi pathway. In addition, LTD4 is able to inhibit lipolysis in adipocytes expressing this chimeric receptor. These results suggest that GPR81 couples to the Gi signaling pathway and that activation of the receptor may regulate adipocyte function and metabolism. Hence, targeting GPR81 may lead to the development of a novel and effective therapy for dyslipidemia and a better side effect profile than nicotinic acid.

Supplementary key words G protein-coupled receptor • dyslipidemia • niacin • GPR109A • free fatty acid • HDL • adipocyte • diabetes

Abbreviations: CysLT2R, cysteinyl leukotriene 2 receptor; GPCR, G protein-coupled receptor; IP, inositol phosphate; LTD4, leukotriene D4; PTX, pertussis toxin


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