Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Liganded Gq/11-activating GPCRs act as GEFs for Gq/11
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Reactome places Gq/11-linked GPCRs upstream of PLC, IP3, and calcium mobilization.
"PLC hydrolyzes phosphatidylinositol (PIP2) to diacyl glycerol (DAG) and inositol triphosphate (IP3)."
Liganded Gi-activating GPCR acts as a GEF for Gi
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Reactome describes nucleotide exchange as the proximal activation step for a Gi-coupled GPCR.
"This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein."
LPA-binding receptors bind LPA
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The cached Reactome summary describes LPA binding by the EDG-family LPA1-3 receptors, not LPAR5 specifically.
"The LPA-binding EDG receptors all bind to the ligand lysophosphatidic acid (LPA), a phospholipid derivative that acts as a potent signaling molecule."
Liganded Gq-activating GPCRs bind inactive heterotrimeric Gq
The Ligand:GPCR:Gq complex dissociates
The Ligand:GPCR:Gi complex dissociates
Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi
Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes.
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GPR92 bound LPA with nanomolar affinity and LPA activation increased phosphoinositide hydrolysis and cAMP production.
"The binding of LPA to GPR92 was of high affinity (K(D) = 6.4 +/- 0.9 nM) and led to an increase in both phosphoinositide hydrolysis and cAMP production."
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The reported human tissue survey found GPR92 broadly expressed and particularly abundant in gastrointestinal intraepithelial cytotoxic T cells.
"It is the most abundant GPCR activated by LPA found in the small intestinal intraepithelial CD8+ cytotoxic T cells."
GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5.
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Heterologously expressed GPR92 showed specific membrane LPA binding and LPA-dependent internalization.
"LPA-dependent receptor internalization following exposure to LPA but not related lysophospholipids was observed."
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LPA activated G12/13 and Gq through GPR92 and increased cAMP in the receptor-expression systems.
"Furthermore, LPA induced concentration-dependent activation of G(12/13) and G(q) and increased cAMP levels."
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LPAR5 expression was enriched in small intestine and sensory dorsal-root ganglia in the reported tissue survey.
"Northern blot and reverse transcriptase-PCR studies indicated a broad low level of expression in many tissues including embryonic brain and enrichment in small intestine and sensory dorsal root ganglia, as well as embryonic stem cells."
Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92.
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FPP, N-arachidonylglycine, and LPA activated GPR92, with ligand-dependent differences in Gq/11 and Gs pathway use.
"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."
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Mutagenesis implicated four GPR92 residues in recognition of FPP and N-arachidonylglycine.
"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."
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GPR92 was detected in mouse and human dorsal-root ganglia with substantial TRPV1 colocalization.
"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."
Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation.
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Mutagenesis identified four residues required for full LPAR5 activation by LPA-related ligands.
"Four residues involved in ligand recognition in LPA(5) were identified as follows: R2.60N mutant abolished receptor activation, whereas H4.64E, R6.62A, and R7.32A greatly reduced receptor activation."
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LPAR5 preferred alkyl glycerol phosphate over LPA, farnesyl phosphates, and N-arachidonoylglycine in the reported structure-activity series.
"SAR revealed that the rank order of agonists is alkyl glycerol phosphate > LPA > farnesyl phosphates >> N-arachidonoylglycine."
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Non-lipid LPAR5 antagonists inhibited human platelet activation.
"Because LPA(5) transcripts are abundant in human platelets, we tested its antagonists on platelet activation and found that these non-lipid LPA(5) antagonists inhibit platelet activation."
GPR92/LPA₅ lysophosphatidate receptor mediates megakaryocytic cell shape change induced by human atherosclerotic plaques.
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LPA caused rapid Rho-kinase-dependent shape change in human megakaryocytic cell lines, with an LPA-species rank order resembling platelets.
"They showed upon LPA stimulation a rapid, Rho-kinase-mediated shape change similar to that of human platelets."
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Selective knockdown showed LPAR5, rather than the other assayed LPA receptors, mediated LPA activation of the megakaryocytic cells.
"Knock-down of individual LPA receptors by siRNA showed that LPA-mediated activation of MK cells was mediated by LPA₅, but not by LPA₁₋₄,₆,₇."
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LPAR5 silencing inhibited megakaryocytic-cell shape change induced by human atherosclerotic plaque material.
"Importantly, we found that human atherosclerotic plaque and lipid-rich core induced shape change of Dami cells, and that this effect was inhibited after LPA₅ silencing."
Targeted deletion of LPA5 identifies novel roles for lysophosphatidic acid signaling in development of neuropathic pain.
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Lpar5-null mice lacked obvious baseline defects but were protected from neuropathic pain after partial sciatic nerve ligation.
"Homozygous null mutants did not show obvious base-line phenotypic defects. However, following PSNL, LPA(5)-deficient mice were protected from developing neuropathic pain."
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Lpar5 loss reduced dorsal-horn phosphorylated CREB without preventing induction of other pain-associated markers.
"They also showed reduced phosphorylated cAMP response element-binding protein expression within neurons of the dorsal horn despite continued up-regulation of the characteristic pain-related markers Caα(2)δ(1) and glial fibrillary acidic protein, results that were distinct from those previously observed for LPA(1) deletion."
Down-regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV-associated nasopharyngeal carcinoma.
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LPAR5 was downregulated in primary nasopharyngeal carcinoma, and reduced LPAR5 promoted LPA-induced migration in NPC cell lines.
"Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines."
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EBV infection or its LMP2A protein was sufficient to reduce LPAR5 in NPC cells.
"Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines."
Structural basis for lysophosphatidic acid recognition and atypical Gα(q) coupling by LPAR5.
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A 2.96-Å cryo-EM structure captured LPAR5 bound to 1-oleoyl-LPA in complex with Gq.
"Here, we report the cryo-EM structure of LPAR5 bound to 1-oleoyl-lysophosphatidic acid (LPA) in complex with Gq at 2.96 Å resolution, revealing a distinct mode of receptor activation and G protein coupling."
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LPA engages a polar headgroup site and a deep hydrophobic tail cavity in LPAR5, with functional support from mutagenesis.
"The phosphate headgroup of LPA forms extensive polar interactions with residues from extracellular loop 2 and transmembrane helices TM5-TM7, while the lipid tail inserts into a deep hydrophobic cavity formed by TM3-TM5. Site-directed mutagenesis confirms the functional importance of these interactions."
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LPAR5 uses a noncanonical Gq interface oriented toward intracellular loop 1 and helix 8 rather than primarily engaging TM6.
"Unlike previously reported GPCR-G protein structures in which the Gα C-terminal α5 helix ("wavy hook") primarily engages TM6, the wavy hook in LPAR5 is positioned toward the intracellular loop 1-helix 8 interface."