LPA<sub>3</sub> receptor | Lysophospholipid (LPA) receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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LPA3 receptor

Target not currently curated in GtoImmuPdb

Target id: 274

Nomenclature: LPA3 receptor

Family: Lysophospholipid (LPA) receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Contents:

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 353 1p22.3 LPAR3 lysophosphatidic acid receptor 3
Mouse 7 354 3 71.03 cM Lpar3 lysophosphatidic acid receptor 3
Rat 7 354 1q55 Lpar3 lysophosphatidic acid receptor 3
Previous and Unofficial Names
Edg7 | LPA receptor 3 | endothelial differentiation gene 7, lysophosphatidic acid G-protein-coupled receptor 7
Database Links
Specialist databases
GPCRDB lpar3_human (Hs), lpar3_mouse (Mm), lpar3_rat (Rn)
Other databases
ChEMBL Target CHEMBL3250 (Hs), CHEMBL4424 (Rn)
Ensembl Gene ENSG00000171517 (Hs), ENSMUSG00000036832 (Mm), ENSRNOG00000015260 (Rn)
Entrez Gene 23566 (Hs), 65086 (Mm), 66025 (Rn)
Human Protein Atlas ENSG00000171517 (Hs)
KEGG Gene hsa:23566 (Hs), mmu:65086 (Mm), rno:66025 (Rn)
OMIM 605106 (Hs)
RefSeq Nucleotide NM_012152 (Hs), NM_022983 (Mm), NM_023969 (Rn)
RefSeq Protein NP_036284 (Hs), NP_075359 (Mm), NP_076459 (Rn)
UniProtKB Q9UBY5 (Hs), Q9EQ31 (Mm), Q8K5E0 (Rn)
Wikipedia LPAR3 (Hs)
Natural/Endogenous Ligands
farnesyl diphosphate
farnesyl monophosphate
LPA

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
LPA Hs Agonist 6.7 pKd 2
⤷ pKd 6.7 [2]
Ki16425 Hs Agonist 6.4 pKi 18
⤷ pKi 6.4 (Ki 3.6x10-7 M) [18]
α-fluoromethylenephosphonate Hs Agonist 9.3 pEC50 25
⤷ pEC50 9.3 [25]
T13 Mm Agonist 9.3 pEC50 15
⤷ pEC50 9.3 (EC50 5x10-10 M) [15]
2-oleoyl-LPA Hs Agonist 8.0 pEC50 3
⤷ pEC50 8.0 [3]
alkyl OMPT Hs Agonist 7.2 pEC50 21
⤷ pEC50 7.2 [21]
OMPT Hs Agonist 7.2 pEC50 10
⤷ pEC50 7.2 [10]
LPA Mm Agonist 6.6 pEC50 15
⤷ pEC50 6.6 (EC50 2.53x10-7 M) [15]
oleoyl-thiophosphate Mm Partial agonist 6.3 pEC50 6
⤷ pEC50 6.3 (EC50 5.46x10-7 M) [6]
NAEPA Mm Agonist <5.3 pEC50 15
⤷ pEC50 <5.3 (EC50 >5x10-6 M) [15]
dioctanoylglycerol pyrophosphate Hs Agonist 7.0 pIC50 8
⤷ pIC50 7.0 (IC50 1.06x10-7 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
farnesyl monophosphate Hs Antagonist 7.3 pKd 16
⤷ pKd 7.3 [16]
farnesyl diphosphate Hs Antagonist 6.8 pKd 16
⤷ pKd 6.8 [16]
dodecyl-thiophosphate Mm Antagonist 7.9 pKi 6
⤷ pKi 7.9 (Ki 1.3x10-8 M) [6]
dodecylphosphate Hs Antagonist 7.1 pKi 23
⤷ pKi 7.1 [23]
Ki16425 Hs Antagonist 6.4 pKi 18
⤷ pKi 6.4 [18]
VPC12249 Hs Antagonist 6.4 pKi 12
⤷ pKi 6.4 [12]
dioctanoylglycerol pyrophosphate Hs Antagonist 5.5 – 7.0 pKi 8,18
⤷ pKi 5.5 – 7.0 (Ki 3.33x10-6 M) [8,18]
farnesyl diphosphate Hs Antagonist 6.8 pIC50 24
⤷ pIC50 6.8 [24]
AM966 Mm Antagonist 6.8 pIC50 22
⤷ pIC50 6.8 [22]
VPC32183 Hs Antagonist 6.8 pIC50 11
⤷ pIC50 6.8 (IC50 1.75x10-7 M) [11]
pIC50 6.8 [11]
farnesyl monophosphate Hs Antagonist 6.3 pIC50 24
⤷ pIC50 6.3 [24]
VPC12249 Hs Antagonist 5.2 – 6.4 pIC50 12,15
⤷ pIC50 5.2 – 6.4 (IC50 6.4x10-6 – 4.28x10-7 M) [12,15]
AM966 Hs Antagonist 5.7 pIC50 22
⤷ pIC50 5.7 [22]
compound 12 [PMID: 19800804] Mm Antagonist 5.5 pIC50 7
⤷ pIC50 5.5 (IC50 2.992x10-6 M) [7]
VPC32179 Hs Antagonist - - 11
⤷ [11]
View species-specific antagonist tables
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
Gq/G11 family 		Adenylate cyclase inhibition
Phospholipase A2 stimulation
Comments:  Others include: phosphatidylinositol-3-kinase, RAS, and MAP kinase activation. For a detailed review please see [4].
References:  14
Tissue Distribution
Heart, testis, prostate, pancreas, lung, ovary, brain
Species:  Human
Technique:  Northern blot
References:  13
Lung, kidney, uterus, oviduct, and testis, small intestine, brain, heart, stomach, placenta, spleen, thymus, embryonic heart, embryonic mesonephros, embryonic otic vesicle
Species:  Mouse
Technique:  Northern blot and in situ hybridisation
References:  17,19,26
Kidney, testis
Species:  Rat
Technique:  Northern blot
References:  13
Expression Datasets

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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
Neurite elongation
Species:  Rat
Tissue:  Neuroblastoma (B103 cell line)
Response measured: 
References:  14
Physiological Functions
Maintenance of proper embryo implantation and spacing
Species:  Mouse
Tissue:  Uterus
References:  5,9,26
LPA,sub>3 acts as a germ cell survival factor during spermatogenesis.
Species:  Mouse
Tissue:  Testes
References:  27
Proliferation of mouse endometrial stromal cells in culture is highly sensitive to lysophosphatidic acid signaling.
Species:  Mouse
Tissue:  Endometrial stromal cells.
References:  1
Physiological Consequences of Altering Gene Expression
Mice with receptor deletion have altered embryo implantation and spacing
Species:  Mouse
Tissue:  Uterus
Technique:  Gene knockouts
References:  5,9,26
Mice with LPA1/LPA2/LPA3 triple deletion show testosterone-dependent reduction in mating activity and sperm production.
Species:  Mouse
Tissue:  Testes
Technique:  Gene knockouts
References:  27
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Lpar3tm1Jch Lpar3tm1Jch/Lpar3tm1Jch
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1929469  MP:0001727 abnormal embryo implantation PMID: 15875025 
Lpar3tm1Jch Lpar3tm1Jch/Lpar3tm1Jch
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1929469  MP:0001711 abnormal placenta morphology PMID: 15875025 
Lpar3tm1Jch Lpar3tm1Jch/Lpar3tm1Jch
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1929469  MP:0001935 decreased litter size PMID: 15875025 
Lpar3tm1Jch Lpar3tm1Jch/Lpar3tm1Jch
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1929469  MP:0009815 decreased prostaglandin level PMID: 15875025 
Lpar3tm1Jch Lpar3tm1Jch/Lpar3tm1Jch
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1929469  MP:0002293 long gestation period PMID: 15875025 
Gene Expression and Pathophysiology Comments
Pharmacological blockade of LPA3 reduces renal ischemia-reperfusion injury in a mouse model, suggesting that LPA3 antagonism may represent a novel intervention for the treatment of ischemic damage in acute renal failure [20].

References

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1. Aikawa S, Kano K, Inoue A, Aoki J. (2017) Proliferation of mouse endometrial stromal cells in culture is highly sensitive to lysophosphatidic acid signaling. Biochem. Biophys. Res. Commun., 484 (1): 202-208. [PMID:28073697]

2. Bandoh K, Aoki J, Hosono H, Kobayashi S, Kobayashi T, Murakami-Murofushi K, Tsujimoto M, Arai H, Inoue K. (1999) Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid. J. Biol. Chem., 274 (39): 27776-85. [PMID:10488122]

3. Bandoh K, Aoki J, Taira A, Tsujimoto M, Arai H, Inoue K. (2000) Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species. Structure-activity relationship of cloned LPA receptors. FEBS Lett., 478 (1-2): 159-65. [PMID:10922489]

4. 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]

5. Diao H, Aplin JD, Xiao S, Chun J, Li Z, Chen S, Ye X. (2011) Altered spatiotemporal expression of collagen types I, III, IV, and VI in Lpar3-deficient peri-implantation mouse uterus. Biol. Reprod., 84 (2): 255-65. [PMID:20864640]

6. Durgam GG, Virag T, Walker MD, Tsukahara R, Yasuda S, Liliom K, van Meeteren LA, Moolenaar WH, Wilke N, Siess W et al.. (2005) Synthesis, structure-activity relationships, and biological evaluation of fatty alcohol phosphates as lysophosphatidic acid receptor ligands, activators of PPARgamma, and inhibitors of autotaxin. J. Med. Chem., 48 (15): 4919-30. [PMID:16033271]

7. Fells JI, Tsukahara R, Liu J, Tigyi G, Parrill AL. (2009) Structure-based drug design identifies novel LPA3 antagonists. Bioorg. Med. Chem., 17 (21): 7457-64. [PMID:19800804]

8. Fischer DJ, Nusser N, Virag T, Yokoyama K, Wang Da, Baker DL, Bautista D, Parrill AL, Tigyi G. (2001) Short-chain phosphatidates are subtype-selective antagonists of lysophosphatidic acid receptors. Mol. Pharmacol., 60 (4): 776-84. [PMID:11562440]

9. Hama K, Aoki J, Inoue A, Endo T, Amano T, Motoki R, Kanai M, Ye X, Chun J, Matsuki N et al.. (2007) Embryo spacing and implantation timing are differentially regulated by LPA3-mediated lysophosphatidic acid signaling in mice. Biol. Reprod., 77 (6): 954-9. [PMID:17823089]

10. Hasegawa Y, Erickson JR, Goddard GJ, Yu S, Liu S, Cheng KW, Eder A, Bandoh K, Aoki J, Jarosz R et al.. (2003) Identification of a phosphothionate analogue of lysophosphatidic acid (LPA) as a selective agonist of the LPA3 receptor. J. Biol. Chem., 278 (14): 11962-9. [PMID:12554733]

11. Heasley BH, Jarosz R, Lynch KR, Macdonald TL. (2004) Initial structure-activity relationships of lysophosphatidic acid receptor antagonists: discovery of a high-affinity LPA1/LPA3 receptor antagonist. Bioorg. Med. Chem. Lett., 14 (11): 2735-40. [PMID:15125924]

12. Heise CE, Santos WL, Schreihofer AM, Heasley BH, Mukhin YV, Macdonald TL, Lynch KR. (2001) Activity of 2-substituted lysophosphatidic acid (LPA) analogs at LPA receptors: discovery of a LPA1/LPA3 receptor antagonist. Mol. Pharmacol., 60 (6): 1173-80. [PMID:11723223]

13. Im DS, Heise CE, Harding MA, George SR, O'Dowd BF, Theodorescu D, Lynch KR. (2000) Molecular cloning and characterization of a lysophosphatidic acid receptor, Edg-7, expressed in prostate. Mol. Pharmacol., 57 (4): 753-9. [PMID:10727522]

14. Ishii I, Contos JJ, Fukushima N, Chun J. (2000) Functional comparisons of the lysophosphatidic acid receptors, LP(A1)/VZG-1/EDG-2, LP(A2)/EDG-4, and LP(A3)/EDG-7 in neuronal cell lines using a retrovirus expression system. Mol. Pharmacol., 58 (5): 895-902. [PMID:11040035]

15. 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]

16. Liliom K, Tsukahara T, Tsukahara R, Zelman-Femiak M, Swiezewska E, Tigyi G. (2006) Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors: inhibition of LPA GPCR and activation of PPARs. Biochim. Biophys. Acta, 1761 (12): 1506-14. [PMID:17092771]

17. McGiffert C, Contos JJ, Friedman B, Chun J. (2002) Embryonic brain expression analysis of lysophospholipid receptor genes suggests roles for s1p(1) in neurogenesis and s1p(1-3) in angiogenesis. FEBS Lett., 531 (1): 103-8. [PMID:12401212]

18. Ohta H, Sato K, Murata N, Damirin A, Malchinkhuu E, Kon J, Kimura T, Tobo M, Yamazaki Y, Watanabe T, Yagi M, Sato M, Suzuki R, Murooka H, Sakai T, Nishitoba T, Im DS, Nochi H, Tamoto K, Tomura H, Okajima F. (2003) Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol. Pharmacol., 64 (4): 994-1005. [PMID:14500756]

19. 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]

20. Okusa MD, Ye H, Huang L, Sigismund L, Macdonald T, Lynch KR. (2003) Selective blockade of lysophosphatidic acid LPA3 receptors reduces murine renal ischemia-reperfusion injury. Am. J. Physiol. Renal Physiol., 285 (3): F565-74. [PMID:12770838]

21. Qian L, Xu Y, Simper T, Jiang G, Aoki J, Umezu-Goto M, Arai H, Yu S, Mills GB, Tsukahara R et al.. (2006) Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA3 receptor-selective agonists. ChemMedChem, 1 (3): 376-83. [PMID:16892372]

22. 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]

23. Virag T, Elrod DB, Liliom K, Sardar VM, Parrill AL, Yokoyama K, Durgam G, Deng W, Miller DD, Tigyi G. (2003) Fatty alcohol phosphates are subtype-selective agonists and antagonists of lysophosphatidic acid receptors. Mol. Pharmacol., 63 (5): 1032-42. [PMID:12695531]

24. 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]

25. Xu Y, Aoki J, Shimizu K, Umezu-Goto M, Hama K, Takanezawa Y, Yu S, Mills GB, Arai H, Qian L et al.. (2005) Structure-activity relationships of fluorinated lysophosphatidic acid analogues. J. Med. Chem., 48 (9): 3319-27. [PMID:15857137]

26. Ye X, Hama K, Contos JJ, Anliker B, Inoue A, Skinner MK, Suzuki H, Amano T, Kennedy G, Arai H et al.. (2005) LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature, 435 (7038): 104-8. [PMID:15875025]

27. Ye X, Skinner MK, Kennedy G, Chun J. (2008) Age-dependent loss of sperm production in mice via impaired lysophosphatidic acid signaling. Biol. Reprod., 79 (2): 328-36. [PMID:18448840]

Contributors

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How to cite this page

Jerold Chun, Yasuyuki Kihara, Yun C. Yung.
Lysophospholipid (LPA) receptors: LPA3 receptor. Last modified on 07/02/2019. Accessed on 21/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=274.