Lysophosphatidic acid (LPA) and its receptors
Introduction
Lysophosphatidic acid (LPA; 1- or 2-acyl-sn-glycerol-3-phosphate) is a bioactive phospholipid with diverse biological functions on many cell types. LPA is detected in serum, plasma, other biological fluids, and tissues including brain [1].
LPA is generated by the action of a number of different enzymes including phospholipase A1 or A2, monoacylglycerol kinase, glycerol-3-phosphate acyltransferase, and autotaxin (ATX), a lysophospholipase D (lysoPLD) [2•]. LPA is catabolized by a number of different pathways that include the actions of lipid phosphate phosphatases or LPA acyltransferase, thus terminating its signaling actions [2•].
LPA elicits its functions through receptors on plasma membranes. So far, there are five G protein-coupled receptors (GPCRs) identified as specific receptors for LPA that are referred to as LPA1, LPA2, LPA3, LPA4, and LPA5 [3, 4, 5, 6, 7, 8]. In addition, recent reports have suggested that three additional GPCRs, GPR87, P2Y5, and P2Y10, may be responsive to LPA [9•, 10•, 11•], although further study is required to validate these observations. Analyses of gene knockout mice for most of the five bona fide receptors have revealed physiological and pathological roles of LPA signaling including brain development [12, 13, 14, 15], neuropathic pain [16], and female and male reproduction [17, 18], to name a few (see below).
This review focuses on the functions of LPA signaling in the nervous system and briefly introduces LPA agonists/antagonists (Figure 1, Figure 2 and Table 2). Because of space limitations, additional characteristics of known LPA receptors are merely summarized in Table 1.
Section snippets
Neural progenitor cells (NPCs)
The processes that mediate central nervous system (CNS) development include proliferation, differentiation, migration, and apoptosis. NPCs proliferate in the ventricular zone (VZ) to expand progenitor pools, and sequentially exit the cell cycle to differentiate into multiple cell types including neurons, astrocytes, and oligodendrocytes (Figure 1). During these processes, the cells change their morphology drastically and migrate out from the VZ toward their final destinations. The restricted
Knockout mice
LPA1-null mice have approximately 50% neonatal lethality, and exhibit craniofacial dysmorphism (shorter snouts and more widely spread eyes) and reduced body mass in survivors [12]. These mice are also characterized by the defects in normal suckling behavior, presumably because of a lack of olfactant detection and/or processing, which accounts for increased neonatal death and decreased postnatal growth. However, no obvious abnormalities in olfactory/vomeronasal epithelia, olfactory bulb, or
LPA signaling in pain
Intraplantar injection of LPA into the mouse hind limb induces peripheral nociception, which is markedly reduced by PTX-pretreatment or substance P receptor antagonist-pretreatment, and partially blocked by LPA1 antisense oligodeoxynucleotide administration [78, 79]. Taken together with a finding that LPA1 mRNA is detected in DRG [79], it appears that LPA induces peripheral nociception through LPA1 and Gi/o by releasing substance P from nociceptor endings.
Intrathecal injection of LPA into mice
LPA receptor agonists/antagonists
In recent years, several groups have reported the generation of agonist and antagonist compounds for LPA receptors that vary in specificities and apparent affinities (Table 2). Several have been reportedly used as study compounds in a number of in vitro applications. Notably, Ki16425 is commercially available and acts as an LPA1/LPA3-specific antagonist [83]. It has been used in cell culture experiments to inhibit such LPA-mediated processes as Ca2+ mobilization, migration, and neurite
Conclusions
LPA signaling is remarkably complex and heterogeneous and has been shown to influence all neural cell types. The developmental, physiological, and pathological significance of these responses in vivo is only beginning to be appreciated, due largely to the studies that have recently been performed on LPA receptor knockout mice. These studies have revealed that LPA influences such processes as the development of the CNS, the function of neurons and glia, and the onset of neuropathic pain.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
Acknowledgements
We thank Danielle Letourneau for critical reading of the manuscript. This work was supported by the National Institute of Mental Health (grant no. MH051699 (JC)), the National Institute of Neurological Disorders and Stroke (grant no. NS048478 (JC)), and the National Institute of Child Health and Human Development (grant no. HD050685 (JC)).
References (93)
- et al.
Stem cell regulation by lysophospholipids
Prostaglandins Other Lipid Mediat
(2007) - et al.
Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid
J Biol Chem
(1999) - et al.
Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family
J Biol Chem
(2003) - et al.
GPR92 as a new G(12/13)- and G(q)-coupled lysophosphatidic acid receptor that increases cAMP, LPA5
J Biol Chem
(2006) - et al.
Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes
J Pharmacol Exp Ther
(2006) - et al.
G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth
Nat Genet
(2008) - et al.
Absence of LPA1 signaling results in defective cortical development
Cereb Cortex
(2008) - et al.
Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma
Cell Mol Life Sci
(2007) - et al.
LPA4/p2y9/GPR23 mediates rho-dependent morphological changes in a rat neuronal cell line
J Biol Chem
(2007) Effects of lysophosphatidic acid on primary cultured chick neurons
Neurosci Lett
(1997)
Lysophosphatidic acid influences the morphology and motility of young, postmitotic cortical neurons
Mol Cell Neurosci
Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse
J Biol Chem
Embryonic brain expression analysis of lysophospholipid receptor genes suggests roles for s1p(1) in neurogenesis and s1p(1–3) in angiogenesis
FEBS Lett
Lysophosphatidic acid induces necrosis and apoptosis in hippocampal neurons
J Neurochem
Lysophosphatidic acid and apoptosis of nerve growth factor-differentiated PC12 cells
J Neurosci Res
Neuroprotective effect of lysophosphatidic acid on AbetaP31–35-induced apoptosis in cultured cortical neurons
Sheng Li Xue Bao
Cyclic phosphatidic acid elicits neurotrophin-like actions in embryonic hippocampal neurons
J Neurochem
Lysophosphatidic acid receptor gene vzg-1/lpA1/edg-2 is expressed by mature oligodendrocytes during myelination in the postnatal murine brain
J Comp Neurol
Regulation of astrocyte morphology by RhoA and lysophosphatidic acid
Exp Cell Res
Pleiotropic effects of lysophosphatidic acid on striatal astrocytes
Glia
Astrocyte spreading in response to thrombin and lysophosphatidic acid is dependent on the Rho GTPase
Glia
LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease
Mol Cell Neurosci
Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development
Mol Cell Biol
Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain
Mol Pain
Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors
Mol Pharmacol
Initial structure–activity relationships of lysophosphatidic acid receptor antagonists: discovery of a high-affinity LPA1/LPA3 receptor antagonist
Bioorg Med Chem Lett
Selective blockade of lysophosphatidic acid LPA3 receptors reduces murine renal ischemia–reperfusion injury
Am J Physiol Renal Physiol
The origin and cell lineage of microglia: new concepts
Brain Res Rev
The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak
Nat Med
LPA1 receptor activation promotes renal interstitial fibrosis
J Am Soc Nephrol
Metabolic pathways and physiological and pathological significances of lysolipid phosphate mediators
J Cell Biochem
Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex
J Cell Biol
Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid
J Biol Chem
The orphan GPCR GPR87 was deorphanized and shown to be a lysophosphatidic acid receptor
Biochem Biophys Res Commun
Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1-phosphate and lysophosphatidic acid receptor
Biochem Biophys Res Commun
Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behaviour
Proc Natl Acad Sci U S A
Characterization of lpa(2) (Edg4) and lpa(1)/lpa(2) (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa(2)
Mol Cell Biol
Deletion of lysophosphatidic acid receptor LPA(1) reduces neurogenesis in the mouse dentate gyrus
Mol Cell Neurosci
Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling
Nat Med
LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing
Nature
Age-dependent loss of sperm production in mice via impaired lysophosphatidic acid signaling
Biol Reprod
A single receptor encoded by vzg-1/lpA1/edg-2 couples to G proteins and mediates multiple cellular responses to lysophosphatidic acid
Proc Natl Acad Sci U S A
Lysophosphatidic acid stimulates cAMP accumulation and cAMP response element-binding protein phosphorylation in immortalized hippocampal progenitor cells
Neuroreport
Lysophosphatidic acid induces clonal generation of mouse neurospheres via proliferation of Sca-1- and AC133-positive neural progenitors
Stem Cells Dev
Lysophosphatidic acid stimulates neuronal differentiation of cortical neuroblasts through the LPA1-G(i/o) pathway
Neurochem Int
Lysophosphatidic acid inhibits neuronal differentiation of neural stem/progenitor cells derived from human embryonic stem cells
Stem Cells
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