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LPA4 receptor

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Target not currently curated in GtoImmuPdb

Target id: 94

Nomenclature: LPA4 receptor

Family: Lysophospholipid (LPA) receptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 370 Xq21.1 LPAR4 lysophosphatidic acid receptor 4
Mouse 7 370 X D Lpar4 lysophosphatidic acid receptor 4
Rat 7 370 Xq31 Lpar4 lysophosphatidic acid receptor 4
Previous and Unofficial Names Click here for help
P2RY9 | P2Y5-like receptor | GPR23 | G protein-coupled receptor 23 | LPA receptor 4 | LPA4 | P2Y purinoceptor 9 | Purinergic receptor 9
Database Links Click here for help
Specialist databases
GPCRdb lpar4_human (Hs), lpar4_mouse (Mm)
Other databases
Alphafold Q99677 (Hs), Q8BLG2 (Mm)
ChEMBL Target CHEMBL5968 (Hs), CHEMBL3321650 (Mm)
Ensembl Gene ENSG00000147145 (Hs), ENSMUSG00000049929 (Mm), ENSRNOG00000002428 (Rn)
Entrez Gene 2846 (Hs), 78134 (Mm), 302378 (Rn)
Human Protein Atlas ENSG00000147145 (Hs)
KEGG Gene hsa:2846 (Hs), mmu:78134 (Mm), rno:302378 (Rn)
OMIM 300086 (Hs)
Pharos Q99677 (Hs)
RefSeq Nucleotide NM_005296 (Hs), NM_175271 (Mm), NM_001106940 (Rn)
RefSeq Protein NP_005287 (Hs), NP_780480 (Mm), NP_001100410 (Rn)
UniProtKB Q99677 (Hs), Q8BLG2 (Mm)
Wikipedia LPAR4 (Hs)
Natural/Endogenous Ligands Click here for help
farnesyl diphosphate
LPA
Comments: Proposed ligand in several publications but not replicated in a recent study based on β-arrestin recruitment [10].

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
LPA Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Hs Agonist 7.3 pKd 8
⤷ pKd 7.3 [8]
LPA Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Mm Agonist 7.3 pKd 8
⤷ pKd 7.3 (Kd 4.5x10-8 M) [8]
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[1-bromo-(3S)-hydrox-4-(palmitoyloxy)butyl]phosphate Small molecule or natural product Hs Antagonist 6.6 pIC50 5
⤷ pIC50 6.6 (IC50 2.66x10-7 M) [5]
farnesyl monophosphate Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 5.8 pIC50 13
⤷ pIC50 5.8 [13]
farnesyl diphosphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Hs Antagonist 5.7 pIC50 13
⤷ pIC50 5.7 [13]
AM966 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.1 pIC50 12
⤷ pIC50 5.1 [12]
Antagonist Comments
Guanine was reported to bind to LPA4 (KD = 29.44 ± 4.07 nM) and shows anti-proliferative effects on human tumor cell lines [2].
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family
Gi/Go family
Gq/G11 family
G12/G13 family 		Adenylyl cyclase stimulation
Comments:  Increase in intracellular calcium and cAMP formation; adenylate cyclase activity may be cell type dependent [16]. Others include: phosphatidylinositol-3-kinase, RAS, Rho. For a detailed review please see [1].
References:  8
Tissue Distribution Click here for help
Ovary, thymus, pancreas, brain, heart, small intestine, testis, prostate, colon, spleen
Species:  Human
Technique:  RT-PCR
References:  8
Embryonic brain, maxillary processes, branchial arches, limb buds, liver, somites, heart, ovary, skin, thymus, bone marrow
Species:  Mouse
Technique:  Northern blot, in situ hybridisation
References:  9
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Stress fiber formation
Species:  Rat
Tissue:  Liver
Response measured:  Stress fiber formation in RH7777 hepatoma cells
References:  16
Cell aggregation and cadherin-dependent cell adhesion
Species:  Rat
Tissue:  Brain
Response measured:  Cell aggregation and cadherin-dependent cell adhesion in B103 neuroblastoma cells
References:  16
Neurite retraction
Species:  Rat
Tissue:  Brain
Response measured:  Neurite retraction in B103 neuroblastoma cells
References:  16
Physiological Functions Click here for help
Negative regulation of cell motility
Species:  Mouse
Tissue:  Fibroblasts
References:  7
Cell-autonomous production of fibronectin
Species:  Human
Tissue:  Pancreatic cancer cells
References:  14
Physiological Consequences of Altering Gene Expression Click here for help
Mice with receptor knockout are hypersensitive to LPA-induced cell migration.
Species:  Mouse
Tissue:  Fibroblast
Technique:  Gene knockouts
References:  7
Mice with receptor knockout demonstrate reduced numbers of hematopoietic stem/progenitor cells and are hypersusceptible to myelosuppresion, due to LPA4-mediated hematopoiesis-supporting activity of bone marrow stromal cells.
Species:  Mouse
Tissue:  Bone marrow PDGFRα (+) stromal cells
Technique:  Gene knockouts
References:  4
Lysophosphatidic acid receptors LPA4 and LPA6 differentially promote lymphocyte transmigration across high endothelial venules in lymph nodes.
Species:  Mouse
Tissue:  Lymphocyte
Technique:  Gene knockouts
References:  3
Mice with receptor knockout attenuates LPA-mediated hypertensive response.
Species:  Mouse
Tissue:  Whole animal
Technique:  Gene knockouts
References:  6
LPA4/LPA6 double KO mice are embryonic lethal due to global vascular deficiencies.
Species:  Mouse
Tissue:  Whole animal
Technique:  Gene knockouts
References:  18
LPA-induced hypertensive response was blocked in LPA4 and LPA6 KO mice.
Species:  Mouse
Tissue:  Whole animal
Technique:  Gene knockout
References:  6
LPA4 KO mice have poor vascular formation with high rate of embryonic lethality.
Species:  Mouse
Tissue:  Whole animal
Technique:  Gene knockouts
References:  11
LPA4 limited adipose tissue expansion and remodeling in obesity.
Species:  Mouse
Tissue: 
Technique:  Gene knockout
References:  15
LPA4 and LPA6 were involved in developmental angiogenesis via LPA4/LPA6-Gα12/13-Rho-ROCK-YAP/TAZ pathway.
Species:  Mouse
Tissue: 
Technique:  Gene knockout
References:  18
LPA4 deficiency attenuates experimental atherosclerosis in mice.
Species:  Mouse
Tissue: 
Technique:  Gene knockout
References:  17

References

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1. Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, Mutoh T, Lin ME, Teo ST, Park KE, Mosley AN, Chun J. (2010) LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol, 50: 157-86. [PMID:20055701]

2. Garozzo R, Zuccarini M, Giuliani P, Di Liberto V, Mudò G, Caciagli F, Ciccarelli R, Ciruela F, Di Iorio P, Condorelli DF. (2022) Guanine inhibits the growth of human glioma and melanoma cell lines by interacting with GPR23. Front Pharmacol, 13: 970891. [PMID:36199684]

3. Hata E, Sasaki N, Takeda A, Tohya K, Umemoto E, Akahoshi N, Ishii S, Bando K, Abe T, Kano K et al.. (2016) Lysophosphatidic acid receptors LPA4 and LPA6 differentially promote lymphocyte transmigration across high endothelial venules in lymph nodes. Int Immunol, 28 (6): 283-92. [PMID:26714589]

4. Igarashi H, Akahoshi N, Ohto-Nakanishi T, Yasuda D, Ishii S. (2015) The lysophosphatidic acid receptor LPA4 regulates hematopoiesis-supporting activity of bone marrow stromal cells. Sci Rep, 5: 11410. [PMID:26090649]

5. Kano K, Arima N, Ohgami M, Aoki J. (2008) LPA and its analogs-attractive tools for elucidation of LPA biology and drug development. Curr Med Chem, 15 (21): 2122-31. [PMID:18781939]

6. Kano K, Matsumoto H, Inoue A, Yukiura H, Kanai M, Chun J, Ishii S, Shimizu T, Aoki J. (2019) Molecular mechanism of lysophosphatidic acid-induced hypertensive response. Sci Rep, 9 (1): 2662. [PMID:30804442]

7. Lee Z, Cheng CT, Zhang H, Subler MA, Wu J, Mukherjee A, Windle JJ, Chen CK, Fang X. (2008) Role of LPA4/p2y9/GPR23 in negative regulation of cell motility. Mol Biol Cell, 19 (12): 5435-45. [PMID:18843048]

8. Noguchi K, Ishii S, Shimizu T. (2003) Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family. J Biol Chem, 278 (28): 25600-6. [PMID:12724320]

9. Ohuchi H, Hamada A, Matsuda H, Takagi A, Tanaka M, Aoki J, Arai H, Noji S. (2008) Expression patterns of the lysophospholipid receptor genes during mouse early development. Dev Dyn, 237 (11): 3280-94. [PMID:18924241]

10. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS et al.. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. J Biomol Screen, 18 (5): 599-609. [PMID:23396314]

11. Sumida H, Noguchi K, Kihara Y, Abe M, Yanagida K, Hamano F, Sato S, Tamaki K, Morishita Y, Kano MR et al.. (2010) LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. Blood, 116 (23): 5060-70. [PMID:20713964]

12. Swaney JS, Chapman C, Correa LD, Stebbins KJ, Bundey RA, Prodanovich PC, Fagan P, Baccei CS, Santini AM, Hutchinson JH et al.. (2010) A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br J Pharmacol, 160 (7): 1699-713. [PMID:20649573]

13. Williams JR, Khandoga AL, Goyal P, Fells JI, Perygin DH, Siess W, Parrill AL, Tigyi G, Fujiwara Y. (2009) Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation. J Biol Chem, 284 (25): 17304-19. [PMID:19366702]

14. Wu C, Rakhshandehroo T, Wettersten HI, Campos A, von Schalscha T, Jain S, Yu Z, Tan J, Mose E, Childers BG et al.. (2023) Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation. Nat Cell Biol, 25 (2): 309-322. [PMID:36646789]

15. Yanagida K, Igarashi H, Yasuda D, Kobayashi D, Ohto-Nakanishi T, Akahoshi N, Sekiba A, Toyoda T, Ishijima T, Nakai Y et al.. (2018) The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity. JCI Insight, 3 (24). [PMID:30568036]

16. Yanagida K, Ishii S, Hamano F, Noguchi K, Shimizu T. (2007) LPA4/p2y9/GPR23 mediates rho-dependent morphological changes in a rat neuronal cell line. J Biol Chem, 282 (8): 5814-24. [PMID:17172642]

17. Yang L, Kraemer M, Fang XF, Angel PM, Drake RR, Morris AJ, Smyth SS. (2019) LPA receptor 4 deficiency attenuates experimental atherosclerosis. J Lipid Res, 60 (5): 972-980. [PMID:30796085]

18. Yasuda D, Kobayashi D, Akahoshi N, Ohto-Nakanishi T, Yoshioka K, Takuwa Y, Mizuno S, Takahashi S, Ishii S. (2019) Lysophosphatidic acid-induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4. J Clin Invest, 129 (10): 4332-4349. [PMID:31335323]

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