ReviewNon-Edg family lysophosphatidic acid (LPA) receptors
Introduction
Lipids are water-insoluble molecules that play five important roles in the body; they are effective energy sources, constituents of cell membranes, molecules covalently attaching to proteins, transporters of lipids such as lipoproteins and are intercellular and intracellular signaling molecules. Bioactive lipids are synthesized enzymatically from membrane lipids [1]. For example, arachidonic acid that is released from membrane phospholipids by cytosolic phospholipase A2α (cPLA2α) is further metabolized to prostaglandins by cyclooxygenases-1, -2 and terminal synthases, and to leukotrienes and monohydroxy acids by lipoxygenases. cPLA2α also produces lyso-platelet-activating factor (lyso-PAF), which is metabolized to another signaling molecule, PAF, by lyso-PAF acetyltransferases. Most bioactive lipids act on cell-surface G-protein-coupled receptors (GPCRs) in an autocrine or paracrine fashion, with short half-lives, usually from seconds to minutes [1].
GPCRs account for 50–60% of direct or indirect targets of current therapeutic drugs [2]. Completion of the human genome project revealed that nearly 800 different human genes encode GPCRs, most of which are considered to bind various extracellular ligands, including lipids, amines and amino acids [3]. The human genome project also identified GPCRs whose endogenous ligands remain to be identified, the so-called orphan GPCRs (Fig. 1). Many groups including academic institutions and pharmaceutical companies are focusing on orphan GPCRs as targets of drug discovery. Indeed, many orphan GPCRs have recently been paired with their endogenous ligands (de-orphanized). However, approximately 120 GPCRs remain to be de-orphanized [3].
Lysophosphatidic acid (LPA; 1- or 2-acyl-sn-glycero-3-phosphate) is a bioactive phospholipid with mitogenic and/or morphological effects on many cell types [4], [5], [6], [7]. In addition, it has been reported that LPA plays important roles in many biological processes, such as the function of the nervous system [8], cancer progression [9], wound healing [10], cardiovascular function [11] and reproduction [12]. Several studies have demonstrated the natural occurrence of multiple molecular species of LPA, as shown in Fig. 2 [4]. Saturated or unsaturated fatty acid is esterified at the sn-1 or sn-2 position of the glycerol backbone, and the sn-1 alkyl or alkenyl ether-linked LPA species are also present. The biological activities of LPA depend on the carbon chain length and the degree of unsaturation, as well as the position and linkage type of the carbon chain attached to the glycerol backbone. At least two LPA production pathways exist [13]. In the first pathway, LPA is extracellularly produced from lysophospholipids, including lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE) and lysophosphatidylserine (LPS), by the plasma enzyme autotaxin (ATX) [14], [15]. In the second pathway, phosphatidic acid (PA) is first generated intracellularly from phospholipids or diacylglycerol and then deacylated by PLA1 or PLA2. Murine plasma/serum LPA was shown to be mainly produced through the action of ATX [16], [17]. LPA was present in human plasma at about 80–100 nM, while the concentrations of LPC, the main substrate of ATX in plasma, were much greater (approximately 1000-fold) than those of LPA [18], [19]. LPA was produced during blood coagulation in vitro that involves lysophospholipid secretion from activated platelets and the enzymatic action of ATX [20]. In humans [18] and rats [21], serum LPA concentrations were considerably greater than plasma LPA concentrations.
Section snippets
Edg family LPA receptors
It was originally thought that the cellular effects of LPA are mediated by the cell-surface GPCRs: LPA1/Edg2/Vzg-1 [22], LPA2/Edg4 [23], and LPA3/Edg7 [24], [25] (Fig. 1). They share 50–57% amino acid identity in humans and, together with five sphingosine-1-phosphate receptors (S1P1/Edg1, S1P2/Edg5, S1P3/Edg3, S1P4/Edg6, and S1P5/Edg8), comprise the endothelial cell differentiation gene (Edg) family (Fig. 1). Several experiments have demonstrated that these Edg family LPA receptors mediate
Finding of a “non-Edg” LPA receptor LPA4
We attempted to de-orphanize several human GPCRs that showed amino acid sequence homology to PAF receptor, which is phylogenetically distant from Edg LPA receptors (Fig. 1). For this purpose, Chinese hamster ovary (CHO) cells were transfected with each orphan GPCR and stably transfected cells were selected with G418. Because it is assumed that GPCRs are preferentially located on the plasma membrane, all the transfected orphan GPCRs were hemagglutinin (HA)-tagged at the N terminus, which is
LPA5
GPR92/GPR93 was an orphan GPCR closely related to LPA4 (Fig. 1), with 28% amino acid identity in humans [44]. The structural similarity led to the identification of this GPCR as a fifth LPA receptor, LPA5 [45], [46]. Chun and colleagues demonstrated that heterologous expression of LPA5 conferred LPA responsiveness in B103 and RH7777 cells: (1) neurite retraction mediated by G12/13 and Rho, (2) receptor internalization, (3) increased [3H]-LPA binding to membrane fractions, (4) increased cAMP
Female reproductive organs and embryos
Our quantitative RT-PCR experiments demonstrated that human LPA4 mRNA was significantly more abundant in the ovary compared with other tissues [32]. Moreover, we analyzed the tissue distribution of LPA4 in mice by Northern blotting and revealed that murine ovary as well as uterus and placenta were rich in LPA4 mRNA (Fig. 4). It is therefore expected that LPA4 might have some physiological functions in female reproduction both in humans and mice. We next used RT-PCR to evaluate the LPA4 mRNA
p2y5 as a sixth LPA receptor, LPA6
Human p2y5 was originally reported in 1996 as an orphan GPCR encoded in an intron of the retinoblastoma (Rb) gene [71]. Shortly thereafter, human LPA4/p2y9/GPR23 was cloned as another orphan GPCR that was closely related to human p2y5 (Fig. 1) [72]. By performing linkage studies, Pasternack et al. and Shimomura et al. recently reported that several mutations in the p2y5 gene underlie autosomal recessive woolly hair/hypotrichosis [73], [74]. These findings clearly revealed the involvement of
Perspectives
In this review, we have summarized the identification of LPA4, LPA5 and LPA6 together with several recent reports on their signaling and function. Further analysis of these non-Edg family LPA receptors will extend our understanding of the biological roles of LPA. Meanwhile, the finding of non-Edg LPA receptor family revealed the complexities of LPA-mediated biology. Now that there are six subtypes of LPA receptors, it is necessary to reevaluate the selectivity of agonists and antagonists. For
Acknowledgments
This work was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports, Culture and Technology of Japan (to S.I.), a grant to the Respiratory Failure Research Group from the Ministry of Health, Labour and Welfare, Japan, and grants-in-aid for Comprehensive Research on Aging and Health from the Ministry of Health, Labour and Welfare, Japan (to S.I.). S.I. was supported by the Center for NanoBio Integration (University of Tokyo).
References (97)
A family of phospholipid autacoids: occurrence, metabolism and bioactions
Prog Lipid Res
(1995)- et al.
Regulation and biological activities of the autotaxin-LPA axis
Prog Lipid Res
(2007) - et al.
Lysophosphatidic acid (LPA) and its receptors
Curr Opin Pharmacol
(2009) - et al.
Roles of lysophosphatidic acid in cardiovascular physiology and disease
Biochim Biophys Acta
(2008) - et al.
Two pathways for lysophosphatidic acid production
Biochim Biophys Acta
(2008) - et al.
Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase
J Biol Chem
(2002) - et al.
Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid
J Biol Chem
(2006) - et al.
A novel colorimetric assay for the determination of lysophosphatidic acid in plasma using an enzymatic cycling method
Clin Chim Acta
(2003) - et al.
Serum lysophosphatidic acid is produced through diverse phospholipase pathways
J Biol Chem
(2002) - et al.
Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid
J Biol Chem
(1998)
Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid
J Biol Chem
Lysophosphatidic acid-induced mitogenesis is regulated by lipid phosphate phosphatases and is Edg-receptor independent
J Biol Chem
Human platelet aggregation induced by 1-alkyl-lysophosphatidic acid and its analogs: a new group of phospholipid mediators?
Biochem Biophys Res Commun
Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family
J Biol Chem
Single nucleotide polymorphism of human platelet-activating factor receptor impairs G-protein activation
J Biol Chem
LPA4/p2y9/GPR23 mediates rho-dependent morphological changes in a rat neuronal cell line
J Biol Chem
LPA(4)/GPR23 is a lysophosphatidic acid (LPA) receptor utilizing G(s)-, G(q)/G(i)-mediated calcium signaling and G(12/13)-mediated Rho activation
J Biol Chem
Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species. Structure-activity relationship of cloned LPA receptors
FEBS Lett
Identification of residues responsible for ligand recognition and regioisomeric selectivity of lysophosphatidic acid receptors expressed in mammalian cells
J Biol Chem
Discovery and mapping of ten novel G protein-coupled receptor genes
Gene
GPR92 as a new G(12/13)- and G(q)-coupled lysophosphatidic acid receptor that increases cAMP, LPA5
J Biol Chem
Identification and characterization of a novel lysophosphatidic acid receptor, p2y5/LPA6
J Biol Chem
Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92
J Biol Chem
Lipid G-protein-coupled receptor ligand identification using beta-arrestin pathhunter assay
J Biol Chem
Lysophospholipid signaling: beyond the EDGs
Biochim Biophys Acta
Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1
J Biol Chem
Cloning and chromosomal mapping of four putative novel human G-protein-coupled receptor genes
Gene
Antagonistic regulation of neurite morphology through Gq/G11 and G12/G13
J Biol Chem
Lysophosphatidic acid stimulates astrocyte proliferation through LPA1
Neurochem Int
From low-density lipoprotein to platelet activation
Int J Biochem Cell Biol
Lysophosphatidic acid-induced platelet shape change proceeds via Rho/Rho kinase-mediated myosin light-chain and moesin phosphorylation
Cell Signal
The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors
Blood
Gene expression profiling for the identification of G-protein coupled receptors in human platelets
Thromb Res
Autotaxin/lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis
J Biol Chem
Cloning of a human heptahelical receptor closely related to the P2Y5 receptor
Biochem Biophys Res Commun
Mutations in the lipase H gene underlie autosomal recessive woolly hair/hypotrichosis
J Invest Dermatol
LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease
Mol Cell Neurosci
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
Identification and characterization of a cell-surface receptor, P2Y15, for AMP and adenosine
J Biol Chem
The recently deorphanized GPR80 (GPR99) proposed to be the P2Y15 receptor is not a genuine P2Y receptor
Trends Pharmacol Sci
Molecular cloning of the human Edg2 protein and its identification as a functional cellular receptor for lysophosphatidic acid
Biochem Biophys Res Commun
The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury
Gastroenterology
The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer
Gastroenterology
Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation
Annu Rev Pharmacol Toxicol
G-protein-coupled receptors and melanoma
Pigment Cell Melanoma Res
Structural diversity of G protein-coupled receptors and significance for drug discovery
Nat Rev Drug Discov
Lysophospholipid receptors
Annu Rev Pharmacol Toxicol
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These authors contributed equally to the review.