LPAR1

Official Full Name

lysophosphatidic acid receptor 1

Organism

Homo sapiens

GeneID

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

Clinical Trial Drug

5 +

Discontinued Drug

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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:

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.
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.
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

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.
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.
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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