ArticleThe Journal of biological chemistry2009
Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed.
- Lysophosphatidic acid receptor 5 in insular cortex as a potential analgesic target in neuropathic pain.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- From Classical to Alternative Pathways of 2-Arachidonoylglycerol Synthesis: AlterAGs at the Crossroad of Endocannabinoid and Lysophospholipid Signaling.Molecules (Basel, Switzerland) · 2024Review
- LPA-Induced Thromboxane A2-Mediated Vasoconstriction Is Limited to Poly-Unsaturated Molecular Species in Mouse Aortas.International journal of molecular sciences · 2024Article
- Article
- Platelets as crucial players in the dynamic interplay of inflammation, immunity, and cancer: unveiling new strategies for cancer prevention.Frontiers in pharmacology · 2024Review
- Synthesis and Biological Evaluation of Lysophosphatidic Acid Analogues Using Conformational Restriction and Bioisosteric Replacement Strategies.ACS omega · 2023Article
- Emerging Roles of Lysophosphatidic Acid in Macrophages and Inflammatory Diseases.International journal of molecular sciences · 2023Review
- GDE7 produces cyclic phosphatidic acid in the ER lumen functioning as a lysophospholipid mediator.Communications biology · 2023Article
- Emerging roles of lysophosphatidic acid receptor subtype 5 (LPAR5) in inflammatory diseases and cancer.Pharmacology & therapeutics · 2023Review
- Isoquinolone derivatives as lysophosphatidic acid receptor 5 (LPA5) antagonists: Investigation of structure-activity relationships, ADME properties and analgesic effects.European journal of medicinal chemistry · 2022Article
- Elucidating the binding mechanism of LPA species and analogs in an LPAJournal of molecular graphics & modelling · 2022Article
- Platelets involved tumor cell EMT during circulation: communications and interventions.Cell communication and signaling : CCS · 2022Review
- Dietary Lactobacillus-Derived Exopolysaccharide Enhances Immune-Checkpoint Blockade Therapy.Cancer discovery · 2022Article
- An LPARFrontiers in pain research (Lausanne, Switzerland) · 2022Article
- Endocannabinoid signaling pathways: beyond CB1R and CB2R.Journal of cell communication and signaling · 2021Review
- Lysolipids in Vascular Development, Biology, and Disease.Arteriosclerosis, thrombosis, and vascular biology · 2021Review
- Bioactive Ether Lipids: Primordial Modulators of Cellular Signaling.Metabolites · 2021Review
- Plasmalogens, platelet-activating factor and beyond - Ether lipids in signaling and neurodegeneration.Neurobiology of disease · 2020Review
- Translational engagement of lysophosphatidic acid receptor 1 in skin fibrosis: from dermal fibroblasts of patients with scleroderma to tight skin 1 mouse.British journal of pharmacology · 2020Article
- Optical Control of Lysophosphatidic Acid Signaling.Journal of the American Chemical Society · 2020Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors.
Funding
Abstract
Lysophosphatidic acid (LPA) is a ligand for LPA(1-3) of the endothelial differentiation gene family G-protein-coupled receptors, and LPA(4-8) is related to the purinergic family G-protein-coupled receptor. Because the structure-activity relationship (SAR) of GPR92/LPA(5) is limited and whether LPA is its preferred endogenous ligand has been questioned in the literature, in this study we applied a combination of computational and experimental site-directed mutagenesis of LPA(5) residues predicted to interact with the headgroup of LPA. 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. We also investigated the SAR of LPA(5) using LPA analogs and other non-lysophospholipid ligands. SAR revealed that the rank order of agonists is alkyl glycerol phosphate > LPA > farnesyl phosphates >> N-arachidonoylglycine. These results confirm LPA(5) to be a bona fide lysophospholipid receptor. We also evaluated several compounds with previously established selectivity for the endothelial differentiation gene receptors and found several that are LPA(5) agonists. A pharmacophore model of LPA(5) binding requirements was developed for in silico screening, which identified two non-lipid LPA(5) antagonists. 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. The present results suggest that selective inhibition of LPA(5) may provide a basis for future anti-thrombotic therapies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.