Review
Non-Edg family lysophosphatidic acid (LPA) receptors

https://doi.org/10.1016/j.prostaglandins.2009.06.001Get rights and content

Abstract

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. In addition, LPA has been reported to play important roles in various biological processes. It was originally thought that the cellular effects of LPA are mediated by three subtypes of G-protein-coupled receptors: LPA1/Edg2, LPA2/Edg4, and LPA3/Edg7. They share 50–57% amino acid identities 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. However, even after finding of the Edg family LPA receptors, the existence of an additional LPA receptor(s) has been implied by several reports. In 2003, we identified p2y9/GPR23 as a fourth LPA receptor, LPA4, which is structurally distant from the Edg family LPA receptors. LPA4/p2y9/GPR23 has stimulated identification of two additional LPA receptors, LPA5/GPR92/GPR93 and LPA6/p2y5. These findings made us aware of the existence of a novel “non-Edg” LPA receptor family. This review article focuses on the identification, properties and possible functions of the non-Edg family LPA receptors: LPA4/p2y9/GPR23, LPA5/GPR92/GPR93 and LPA6/p2y5.

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).

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