title: Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92.
abstract: 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.
authors.affiliation: Laboratory of G Protein-Coupled Receptors and Department of Physiology, Korea University College of Medicine, Seoul, Korea.
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Yoon
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Moon
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.forename: Ju Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Sunoh
authors.initials: S
authors.lastname: Kim
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.forename: David K
authors.initials: DK
authors.lastname: O'Dell
authors.forename: J Michael
authors.initials: JM
authors.lastname: Walker
authors.forename: Heung Sik
authors.initials: HS
authors.lastname: Na
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Hyuk Bang
authors.initials: HB
authors.lastname: Kwon
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
mesh_terms: D001095:Arachidonic Acids / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D008246:Lysophospholipids / Q000737:chemistry; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000737:chemistry*; D049368:Receptors, Lysophosphatidic Acid / Q000737:chemistry*; D012717:Sesquiterpenes / Q000737:chemistry*; D015398:Signal Transduction; D014018:Tissue Distribution
chemical_list: D001095:Arachidonic Acids; D007295:Inositol Phosphates; C512992:LPAR5 protein, human; D008024:Ligands; D008246:Lysophospholipids; C465623:N-arachidonylglycine; D011106:Polyisoprenyl Phosphates; D049368:Receptors, Lysophosphatidic Acid; D012717:Sesquiterpenes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C004808:farnesyl pyrophosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C032881:lysophosphatidic acid; D002118:Calcium; D005998:Glycine