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LPAR1


Official Full Name
lysophosphatidic acid receptor 1
Organism
Homo sapiens
Gene ID
1902
Background
The integral membrane protein encoded by this gene is a lysophosphatidic acid (LPA) receptor from a group known as EDG receptors. These receptors are members of the G protein-coupled receptor superfamily. Utilized by LPA for cell signaling, EDG receptors mediate diverse biologic functions, including proliferation, platelet aggregation, smooth muscle contraction, inhibition of neuroblastoma cell differentiation, chemotaxis, and tumor cell invasion. Many transcript variants encoding a few different isoforms have been identified for this gene. [provided by RefSeq, Oct 2020]
Synonyms
EDG2; LPA1; VZG1; edg-2; vzg-1; Gpcr26; Mrec1.3; rec.1.3
Bio Chemical Class
GPCR rhodopsin
Protein Sequence
MAAISTSIPVISQPQFTAMNEPQCFYNESIAFFYNRSGKHLATEWNTVSKLVMGLGITVCIFIMLANLLVMVAIYVNRRFHFPIYYLMANLAAADFFAGLAYFYLMFNTGPNTRRLTVSTWLLRQGLIDTSLTASVANLLAIAIERHITVFRMQLHTRMSNRRVVVVIVVIWTMAIVMGAIPSVGWNCICDIENCSNMAPLYSDSYLVFWAIFNLVTFVVMVVLYAHIFGYVRQRTMRMSRHSSGPRRNRDTMMSLLKTVVIVLGAFIICWTPGLVLLLLDVCCPQCDVLAYEKFFLLLAEFNSAMNPIIYSYRDKEMSATFRQILCCQRSENPTGPTEGSDRSASSLNHTILAGVHSNDHSVV
Open
Disease
Fibrosis, Idiopathic interstitial pneumonitis, Psoriasis, Systemic sclerosis
Approved Drug
0
Clinical Trial Drug
5 +
Discontinued Drug
0

Cat.No. Product Name Price
SHW002774 shRNA set against Chicken LPAR1 (NM_001115082) Inquiry
SHH023717 shRNA set against Human EDG2(NM_057159.2) Inquiry
SHH023737 shRNA set against Human EDG2(NM_001401.3) Inquiry
SHH023755 shRNA set against Human EDG2(NM_057159.2) Inquiry
SHH023771 shRNA set against Rat Edg2(NM_053936.3) Inquiry
SHH072461 shRNA set against Rat G10(NM_053556.1) Inquiry
SHH248486 shRNA set against Human BUD31 (NM_003910.3) Inquiry
SHH248490 shRNA set against Mouse BUD31 (NM_001008705.1) Inquiry
SHH248494 shRNA set against Rat BUD31 (NM_053556.1) Inquiry
SHH271721 shRNA set against Human CTTNBP2NL (NM_018704.2) Inquiry
SHH271725 shRNA set against Mouse CTTNBP2NL (NM_030249.4) Inquiry
SHH271729 shRNA set against Rat CTTNBP2NL (NM_001107712.2) Inquiry
SHH333403 shRNA set against Mouse LPAR1 (NM_010336.2) Inquiry
SHH333407 shRNA set against Rat LPAR1 (NM_053936.3) Inquiry
SHW007033 shRNA set against Danio rerio BUD31 (NM_001003860) Inquiry
SHW007131 shRNA set against Danio rerio LPAR1 (NM_001004502) Inquiry
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OE-PNDC000143 Human LPAR1 Nanodisc Inquiry
Cat.No. Product Name Price
MiUTR4H-TG02458 CTTNBP2NL miRNA 3'UTR clone Inquiry
CDCR314686 Human LPAR1 ORF Clone(NM_057159.2) Inquiry
CDCR248822 Mouse Lpar1 ORF Clone(NM_010336.2) Inquiry
CDFG007227 Human LPAR1 cDNA Clone(NM_057159.2) Inquiry
CDFH010583 Human LPAR1 cDNA Clone(NM_001401.3) Inquiry
CDCR058636 Human LPAR1 ORF clone (NM_001401.3) Inquiry
MiUTR3H-06002 BUD31 miRNA 3'UTR clone Inquiry
CDFR007356 Rat Cttnbp2nl cDNA Clone(NM_001107712.2) Inquiry
CDFR013646 Rat Lpar1 cDNA Clone(NM_053936.3) Inquiry
MiUTR1H-03106 LPAR1 miRNA 3'UTR clone Inquiry
MiUTR1M-02321 BUD31 miRNA 3'UTR clone Inquiry
MiUTR1R-01643 LPAR1 miRNA 3'UTR clone Inquiry
MiUTR1R-01997 BUD31 miRNA 3'UTR clone Inquiry
MiUTR3H-04838 LPAR1 miRNA 3'UTR clone Inquiry
CDFR013280 Rat Bud31 cDNA Clone(NM_053556.1) Inquiry
CDCS410258 Human LPAR1 ORF Clone (BC036034) Inquiry
CDCS414851 Human CTTNBP2NL ORF Clone (BC016029) Inquiry
CDCS410259 Human LPAR1 ORF Clone (BC073167) Inquiry
CDCR374431 Rat Cttnbp2nl ORF Clone(NM_001107712.2) Inquiry
CDCR380357 Rat Bud31 ORF Clone(NM_053556.1) Inquiry
CDCR271961 Mouse Lpar1 ORF Clone(NM_172989.1) Inquiry
CDCR263539 Mouse Cttnbp2nl ORF Clone(NM_030249.4) Inquiry
CDCR239710 Mouse Cttnbp2nl ORF Clone(NM_001163333.1) Inquiry
CDCR239709 Mouse Cttnbp2nl ORF Clone(NM_001163332.1) Inquiry
CDCR035836 Mouse Bud31 ORF clone (NM_001008705.1) Inquiry
CDCB196771 Rabbit LOC103347662 ORF clone (XM_008254301.1) Inquiry
CDCB189919 Rabbit BUD31 ORF clone (XM_008248923.1) Inquiry
CDCB187831 Rabbit CTTNBP2NL ORF clone (XM_002715769.2) Inquiry
CDCB184834 Rabbit LPAR1 ORF clone (XM_008254984.1) Inquiry
CDCB168606 Danio rerio LPAR1 ORF Clone (NM_001004502) Inquiry
CDCB168508 Danio rerio BUD31 ORF Clone (NM_001003860) Inquiry
CDCB164249 Chicken LPAR1 ORF Clone (NM_001115082) Inquiry
CDCR380519 Rat Lpar1 ORF Clone(NM_053936.3) Inquiry
CDCB156171 Cynomolgus BUD31 ORF clone Inquiry

Detailed Information

Lysophosphatidic acid receptor 1 (LPAR1), also known as Endothelial differentiation gene-2 receptor (Edg2), was first discovered in the developing brain in 1996. Research showed that LPAR1 is enriched in the ventricular zone (VZ) of the embryonic cerebral cortex. Subsequently, researchers identified five other receptors in the LPAR family, including LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6, all of which are expressed in the central nervous system (CNS).

LPAR1 is a 41 kDa protein composed of 364 amino acids, with its gene located on human chromosome 9 (9q31.3). As a G protein-coupled receptor (GPCR) on the cell surface, LPAR1 has a seven-transmembrane structure, forming 3 extracellular loops and 3 intracellular loops. It has a putative nuclear translocation signal, an N-terminal acidic domain, and a cysteine-rich C-terminal domain containing a putative zinc finger structure. The polypeptide sequence of LPAR1 is highly conserved during evolution, suggesting that it may be an important regulator of general nuclear function.

LPAR1 is widely expressed in various tissues and organs of the human body, particularly with high mRNA levels in the brain, heart, colon, small intestine, and placenta, but relatively lower in other organs and tissues. In the central nervous system, LPAR1 is present on various cell types, such as astrocytes, oligodendrocytes, microglia, and neurons.

Figure 1: LPA signaling activates distinct G protein pathways with varied roles in the central nervous system (CNS). Figure 1. LPA signaling causes G proteins to play different roles in the CNS. (Xiao D, et al., 2021)

LPAR1 Ligands and Signaling Pathways

The ligand for LPAR1 is lysophosphatidic acid (LPA), a bioactive phospholipid with a 1-acyl-sn-glycerol-3-phosphate structure. LPA is an extracellular signaling molecule present in all eukaryotic tissues and plasma, produced during cell membrane synthesis, and mediates extracellular signal transduction through interaction with specific G protein-coupled receptors.

After binding to LPAR1, LPA couples with G proteins (Gi/0, Gαq, and G12/13), subsequently activating second messenger pathways, participating in the regulation of cell proliferation, migration, survival, apoptosis, and morphological changes. Specifically:

  1. LPAR1 can efficiently couple to the yeast heterotrimeric G-protein in response to LPA binding and activate the yeast mitogen-activated protein kinase (MAPK) pathway.
  2. LPAR1 can also couple with Gi/o to activate Ras and then the MEK-ERK pathway. Subsequently, ERK acts to inhibit the tuberous sclerosis complex (TSC1/2), thereby increasing GTP loading on Ras homolog enriched in brain (Rheb) and thus activating mTORC1. mTORC1 then phosphorylates downstream targets, such as S6K1 and eukaryotic initiation factor 4E-binding protein (4E-BP1), ultimately leading to increased mRNA translation.
  3. LPAR1 couples to Gα12/13 to mediate Rho-GEF/RhoA-GTP and thus affect actomyosin contraction and couples to Gi to mediate PI3Kβ/Tiam1/Rac-GTP and therefore affect cell spreading and lamellipodia formation, thus altering cell migration and motility.

Notably, LPAR1 with the P308S, I310T, and Y311H mutations might not interact with helix 8, leading to structural defects and retention of LPAR1 in the endoplasmic reticulum. In addition, mutation of LPAR1 can alter its intracellular activities, such as Ca2+ mobilization, inhibition of cAMP formation, and cytoskeletal changes, which are mainly mediated by Gq, Gi/o, and G12/13, respectively.

Development Progress of LPAR1 Target Drugs

The company with the fastest research in this field is BMS, with reported compounds including BMS-986020, BMS-986234, and BMS-986278. All three compounds are effective antagonists of LPA1 but have different chemical structures.

Phase II clinical trial (NCT01766817) results showed that, compared to placebo, IPF patients receiving BMS-986020 600 mg BID treatment had significantly slower decline in pulmonary fibrosis scores from baseline to 26 weeks. However, this Phase II trial was forced to terminate due to hepatobiliary toxicity in clinical subjects. In addition to hepatobiliary toxicity, BMS-986020 has an unstable structure and is easily metabolized, resulting in very large clinical doses.

After restructuring, researchers obtained BMS-986278. BMS-986278 exhibits ideal physicochemical properties and metabolic stability, effectively inhibits LPA-stimulated calcium flux in human lung fibroblasts, significantly inhibits bleomycin-induced pulmonary fibrosis, and has significantly reduced potential hepatotoxicity. According to the results reported by the European Respiratory Society in 2023, the FDA has granted BMS-986278 breakthrough therapy designation, and BMS-986278 is currently in Phase III trials in IPF patients.

Besides BMS, in 2023, Amgen spent $27.8 billion to acquire Horizon Therapeutics, thereby obtaining its LPAR1 target drug fipaxalparant (HZN-825), which is currently in Phase II clinical research (NCT05032066).

References

  1. Xiao D, Su X, Gao H, et al. The Roles of Lpar1 in Central Nervous System Disorders and Diseases. Front Neurosci. 2021 Jul 27;15:710473.
  2. Sumitomo A, Siriwach R, Thumkeo D, et al. LPA Induces Keratinocyte Differentiation and Promotes Skin Barrier Function through the LPAR1/LPAR5-RHO-ROCK-SRF Axis. J Invest Dermatol. 2019 May;139(5):1010-1022.
  3. Luo YL, Li Y, Zhou W, et al. Inhibition of LPA-LPAR1 and VEGF-VEGFR2 Signaling in IPF Treatment. Drug Des Devel Ther. 2023 Sep 2;17:2679-2690.
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