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Details for receptor: Lysophosphatidic acid receptor 1

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EndoNet ID: ENR00756

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Synonyms

  • edg2
  • Lysophosphatidic acid receptor 1
  • LPA receptor 1
  • LPAR1
  • Lysophosphatidic acid receptor Edg-2

General information

  • Belongs to the G-protein coupled receptor 1 family.
  • Seems to be coupled to the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins.
  • Stimulates phospholipase C (PLC) activity in a manner that is dependent on RALA activation. [1]
  • LPA1 shows little selectivity for the number and position of double bonds in the acyl chain of their lipid ligands. [2]

Links to other resources

UniProt Q92633
Ensembl ENST00000449490

Subunit information

Subunit (1 times)

Sequence 
MAAISTSIP VISQPQFTA MNEPQCFYN 
ESIAFFYNR SGKHLATEW NTVSKLVMG 
LGITVCIFI MLANLLVMV AIYVNRRFH 
FPIYYLMAN LAAADFFAG LAYFYLMFN 
TGPNTRRLT VSTWLLRQG LIDTSLTAS 
VANLLAIAI ERHITVFRM QLHTRMSNR 
RVVVVIVVI WTMAIVMGA IPSVGWNCI 
CDIENCSNM APLYSDSYL VFWAIFNLV 
TFVVMVVLY AHIFGYVRQ RTMRMSRHS 
SGPRRNRDT MMSLLKTVV IVLGAFIIC 
WTPGLVLLL LDVCCPQCD VLAYEKFFL 
LLAEFNSAM NPIIYSYRD KEMSATFRQ 
ILCCQRSEN PTGPTEGSD RSASSLNHT 
ILAGVHSND HSVV
UniProt Q92633-1

Binding hormones

  • lysophosphatidic acid
    • Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities.

Anatomical structures with this receptor

  • brain

    Induced phenotypes

    • cerebral cortex development
      • LPA1 was identified initially in studies of genes that are involved in the development of the cerebral cortex. [2]
    • positive regulation of cytoskeleton organization
      • EDG2 overexpression in a neuronal-like cell exaggerated LPA-stimulated cytoskeletal changes (Rho-mediated). [3]
    • regulation of actin filament bundle assembly
      • In Xenopus LPA1 and LPA2 homologs were reported to regulate normal cortical actin assembly. [4]
    • brain development
      • LPA1 deficiency resulted in defects in cortical development, including reduced proliferative populations and increased cortical apoptosis. [5]
    • inhibition of adenylate cyclase activity by G-protein signaling pathway
      • EDG2 overexpression in a neuronal-like cell exaggerated LPA-stimulated inhibition of adenylate cyclase. [3]

  • heart

  • colon

  • small_intestine

  • placenta

  • prostate

  • ovary

    Induced phenotypes

    • Ovarian cancer
      • In addition to the involvement of LPA2, there is evidence for contribution of LPA1 to the tumorigenic activity of LPA. Genetic and pharmacological inhibition of LPA1 has been shown to reduce the proliferation and metastasis of OCCs. [6]

  • pancreas

  • testis

  • spleen

  • skeleton_muscle

  • kidney

    Induced phenotypes

    • fibrosis
      • Fibrosis, the formation of excess fibrous connective tissues, is associated with a number of pathological conditions. Recently, a new aspect of LPA1 signaling has been uncovered in tubulointerstitial fibrosis (TIF), suggesting LPA1 signaling as a new therapeutic target in this disease. [7]
      • Likewise, in a unilateral ureteral obstruction model for TIF, the resulting kidney fibrosis was accompanied by an increase in LPA accumulation and LPA1 expression. [7]
      • Fibrosis was markedly reduced in Lpar1−/− mice or following treatment with Ki16425, an LPA1/LPA3 antagonist. [7]

  • vascularendothelial_cell

    Induced phenotypes

    • positive regulation of angiogenesis
      • LPA is a mediator in angiogenesis. An initial characterization of knockout mice revealed the presence of frontal cephalic hemorrhages in Lpar1-deficient mice. [8]
    • cell maturation
      • LPA is a mediator in vascular maturation. An initial characterization of knockout mice revealed the presence of frontal cephalic hemorrhages in Lpar1-deficient mice. [8]
    • induction of cytokine expression
      • Lysophosphatidic acid induces expression of cytokines (MCP-1, IL-8, IL-1β) in vascular endothelial cells. [9]
      • Expression of inflammatory cytokines play important role in development of atherosclerosis and thrombosis. [9]
    • negative regulation of apoptosis
      • S1P protects VECs from serum-deprived apoptosis by nitric oxide production through S1P1 receptor. [10]

  • smooth_muscle_cell

    Induced phenotypes

    • negative regulation of smooth muscle cell migration
      • LPA1 and LPA2 were found to exhibit opposing effects on primary VSMCs derived from knockout mice. The migration of SMCs was increased in Lpar1−/− mice but attenuated in Lpar1−/−/Lpar2−/− mice, thus identifying LPA1 and LPA2 as negative and positive chemotactic mediators, respectively. [11]
      • LPA induces the proliferation and migration of vascular smooth muscle cells (VSMCs). [12]
    • smooth muscle cell dedifferentiation
      • Lysophosphatidic acid influences vascular cell functions, including smooth muscle cell de-differentiation. [13]
    • smooth muscle cell migration
      • Lysophosphatidic acid influences vascular cell functions, including smooth muscle cell migration. [13]
    • regulation of vascular smooth muscle cell proliferation
      • Lysophosphatidic acid influences vascular cell functions, including smooth muscle cell proliferation. [13]
    • positive regulation of smooth muscle proliferation
      • Overexpression of S1PR1 in VSMCs enhances mitogenic responses to S1P. [14]

  • hair_follicle

  • continuous_vascular_endothelial_cell_of_blood_vessels_and_lymphatics

  • osteoblast

    Induced phenotypes

    • skeletal system development
      • The finding of craniofacial deformities in mice in which the gene for edg-2 has been deleted suggests that phospholipids may participate in skeletal development. [8]

  • lung

    Induced phenotypes

    • pulmonary fibrosis
      • Fibrosis, the formation of excess fibrous connective tissues, is associated with a number of pathological conditions. Recently, a new aspect of LPA1 signaling has been uncovered in pulmonary fibrosis, suggesting LPA1 signaling as a new therapeutic target in this disease. LPA levels were remarkably increased in bronchoalveolar lavage fluid after bleomycin-induced lung injury and resulted in pulmonary fibrosis, vascular leakage, and mortality. These pathologies were markedly reduced in Lpar1-deficient mice. [15]

  • muscle

  • stomach

  • oligodendrocyte

    Induced phenotypes

    • myelin formation in the central nervous system
      • A significant role for LPA signaling in myelination was suggested by the Lpar1 gene expression pattern that spatially and temporally correlated with oligodendrocyte myelination. [16]
      • LPA has a positive effect on process formation and myelin basic protein production in oligodendrocytes. [17]
    • cell maturation
      • A significant role for LPA signaling in myelination was suggested by the Lpar1 gene expression pattern that spatially and temporally correlated with oligodendrocyte maturation. [18]
      • Oligodendrocytes, the myelin-forming glial cells in the CNS, express LPA1 and LPA3 during differentiation. [18]

  • Schwann_cell

    Induced phenotypes

    • regulation of myelination
      • Schwann cells (SCs) are the myelinating cells of the peripheral nervous system. SCs express LPA1 and activation of this receptor is known to affect processes associated with myelination. [19]
    • regulation of actin cytoskeleton organization
      • LPA also induced dynamic regulation of the actin cytoskeleton and cellular adhesion properties in primary rat SCs, which suggests a critical role for LPA signaling in SC motility and myelination. [19]
    • negative regulation of glial cell apoptosis
      • LPA-mediated SC survival was confirmed in vivo, as mice deficient for LPA1 revealed increased apoptosis of SCs in the sciatic nerves. [8]
    • myelin formation in the peripheral nervous system
      • In addition to the role for myelination during developmental stages, evidence indicates a role for LPA signaling in remyelination after injuries such as neuropathic pain and nerve transection where LPA1 is upregulated despite very low levels under basal conditions. [20]

  • thymus

  • fetal brain

    Induced phenotypes

    • brain development
      • LPA1 is implicated in brain formation during embryonic development. [21]

  • neuron

    Induced phenotypes

    • negative regulation of neuron projection development
      • Overexpression of LPA1 results in neurite retraction and cell rounding when stimulated with LPA [22]
    • regulation of cell proliferation
      • LPA signaling controls proliferation and differentiation of primary neuroprogenitor cells and neurosphere cultures via LPA1. [23]

  • hippocampus

    Induced phenotypes

    • positive regulation of neuron differentiation
      • LPA signaling controls differentiation of immortalized hippocampal progenitor cells via LPA4. [24]

  • astrocyte

    Induced phenotypes

    • astrocyte development
      • A study using LPA1-null astrocytes clearly identified the involvement of this receptor in LPA-mediated astrocyte proliferation. [25]
      • Astrocytes primed by LPA increase neuronal differentiation, likely through as yet unidentified soluble factors, and this activity is dependent on activation of LPA1 and in astrocytes. [26]

  • microglial_cell_in_central_nervous_system

    Induced phenotypes

    • membrane hyperpolarization
      • Several cellular functions of LPA signaling in microglia have been observed, including cell membrane hyperpolarization. [27]
    • positive regulation of chemokinesis
      • Several cellular functions of LPA signaling in microglia have been observed, including enhanced chemokinesis. [27]
    • membrane ruffling
      • Several cellular functions of LPA signaling in microglia have been observed, including membrane ruffling. [28]
    • positive regulation of cytokine production
      • Several cellular functions of LPA signaling in microglia have been observed, including growth factor upregulation. [27]
    • regulation of glia cell proliferation
      • Several cellular functions of LPA signaling in microglia have been observed, including proliferation. [27]

  • central_nerve_system_element

    Induced phenotypes

    • schizophrenia
      • An intriguing link may exist between LPA signaling and neurological diseases such as schizophrenia, on the basis of phenotypic and molecular similarities. Craniofacial dysmorphism, defects in prepulse inhibition, and widespread brain alterations in serotonin neurotransmitter levels are present in both Lpar1-deficient mice and patients suffering from schizophrenia. [29]

  • nerve

    Induced phenotypes

    • sensory perception of pain
      • Furthermore, Lpar1-deficient mice are resistant to neuropathic pain induced by partial sciatic nerve ligation. [20]
      • It was shown that LPA is able to initiate neuropathic pain in the peripheral nervous system, which occurs through the activation of LPA1 and subsequent release of the pronociceptive factor substance P. [30]

  • umbilical_vein_endothelial_cells

    Induced phenotypes

    • positive regulation of cell death
      • In human umbilical vein endothelial cells (as well as porcine cerebral microvascular cells), LPA was found to induce oncotic cell death via protein nitrosylation. This endothelial cytotoxicity was reproduced in brain explants and retinas in vivo that exhibit diminished vasculature. This was reported to be LPA1 mediated. [31]

  • platelet

    Induced phenotypes

    • atherosclerosis
      • The effect of LPA on platelets may be species-specific, because LPA was found to inhibit platelet activation in mice. [32]
      • LPA has been implicated in the development of atherosclerosis during early (barrier dysfunction and monocyte adhesion of the endothelium) and later phases (platelet activation and thrombosis). [33]
      • LPA was found to accumulate in the thrombogenic lipid-rich core of atherosclerotic plaques. Pharmacological studies identified LPA1 as primary mediator of LPA-induced platelet activation. [34]

  • fibroblast

    Induced phenotypes

    • wound healing
      • Several lines of evidence suggest that LPA mediates wound healing.
      • LPA induced the closure of wounded endothelial monolayers in vitro. [35]
      • In vivo LPA application promoted repair processes in cutaneous wounds. [36]
      • In vivo LPA application promoted repair processes in intestinal wounds. [37]
      • Migration of fibroblasts into the fibrin wound matrix is an essential step in the wound-healing process in injured tissues, and LPA1 signaling regulates migration of mouse embryonic fibroblasts. [15]

  • T-lymphocyte

    Induced phenotypes

    • regulation of T cell chemotaxis
      • In activated T cells where LPA2 is downregulated while LPA1 is upregulated, LPA inhibits chemotaxis through LPA1. [38]
    • positive regulation of interleukin-2 production
      • In activated T cells where LPA2 is downregulated while LPA1 is upregulated, LPA activates IL-2 production through LPA1. [38]
    • positive regulation of interleukin-13 production
      • In activated T cells where LPA2 is downregulated while LPA1 is upregulated, LPA upregulates IL-13 through LPA1. [39]
    • positive regulation of activated T cell proliferation
      • In activated T cells where LPA2 is downregulated while LPA1 is upregulated, LPA activates cell proliferation through LPA1. [38]

  • breast

    Induced phenotypes

    • breast cancer
      • In addition to the involvement of LPA2, there is evidence for contributions of LPA1 to the tumorigenic activity of LPA. Genetic and pharmacological inhibition of LPA1 has been shown to reduce the proliferation and metastasis of breast cancer cells in vitro and in vivo. [6]

  • digestive_system

    Induced phenotypes

    • gastrointestinal cancer
      • LPA is implicated in the progression of gastrointestinal cancers. LPA stimulates proliferation, migration, and invasion primarily through the activation of LPA1. [40]

  • preadipocyte

    Induced phenotypes

    • negative regulation of fat cell differentiation
      • LPA1 signaling appears to be antiadipogenic because stimulation of LPA1 signaling inhibits the differentiation of preadipocytes. This inhibitory effect is the result of the downregulation of PPARγ2. [41]
    • positive regulation of cell motility
      • The first indications that LPA is involved in adipogenesis were based on the observations that LPA is released by adipocytes, but not by preadipocytes, in vivo and in vitro, and LPA stimulates motility of preadipocytes through LPA1. [42]
    • positive regulation of fat cell proliferation
      • The first indications that LPA is involved in adipogenesis were based on the observations that LPA is released by adipocytes, but not by preadipocytes, in vivo and in vitro, and LPA stimulates proliferation of preadipocytes through LPA1. [43]
    • positive regulation of glucose import
      • It is indicated that LPA signaling, possibly through LPA1, regulates blood glucose levels by enhancing glucose uptake by adipocytes and thereby resulting in an LPA-induced glucose-lowering effect. [44]

  • white_matter

Reference