Elucidation of signaling and functional activities of an orphan GPCR, GPR81.
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 D(4) (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.
Ge
Hongfei
H
Amgen, Inc., South San Francisco, CA 94080, USA.
Weiszmann
Jennifer
J
Reagan
Jeff D
JD
Gupte
Jamila
J
Baribault
Helene
H
Gyuris
Tibor
T
Chen
Jin-Long
JL
Tian
Hui
H
Li
Yang
Y
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D006224:Cricetinae; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D017998:Leukotriene D4 / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation
C529424:Hcar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D017998:Leukotriene D4; D019206:GTP-Binding Protein alpha Subunits, Gi-Go