Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92.
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.
Oh
Da Young
DY
Laboratory of G Protein-Coupled Receptors and Department of Physiology, Korea University College of Medicine, Seoul, Korea.
Yoon
Jung Min
JM
Moon
Mi Jin
MJ
Hwang
Jong-Ik
JI
Choe
Han
H
Lee
Ju Yeon
JY
Kim
Jae Il
JI
Kim
Sunoh
S
Rhim
Hyewhon
H
O'Dell
David K
DK
Walker
J Michael
JM
Na
Heung Sik
HS
Lee
Min Goo
MG
Kwon
Hyuk Bang
HB
Kim
Kyungjin
K
Seong
Jae Young
JY
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
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