Submitted on November 8, 2007
Revised on December 19, 2007
Accepted on January 2, 2008
Elucidation of signaling and functional activities of an orphan GPCR-GPR81
Hongfei Ge, Jennifer Weiszmann, Jeff D. Reagan, Jamila Gupte, Helene Baribault, Tibor Gyuris, Jin-Long Chen, Hui Tian, and Yang Li
Amgen, Inc., South San Francisco, CA 94080
Corresponding Author: yangl{at}amgen.com
GPR81 is an orphan G protein-coupled receptor (GPCR) that has high degree of homology to nicotinic acid receptor, GPR109A. GPR81 expression is highly enriched and specific in adipocytes. However, the function and signaling properties of GPR81 are unknown due to 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 Gi signaling pathway. We have also constructed a chimeric receptor that expresses the extracellular domains of CysLT2R and intracellular domains of GPR81. We show that CysLT2R ligand, LTD4, is able to activate this chimeric receptor through activation of Gi pathway. In addition, LTD4 is able to inhibit lipolysis in adipocytes expressing this chimeric receptor. These results suggest that GPR81 couples to Gi signaling pathway and 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.
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