TY - JOUR
AU - Ishii, Satoshi
AB - Abstract Lysophosphatidic acid (LPA) is a bioactive lipid mediator with diverse physiological and pathological actions on many types of cells. Originally, LPA was thought to elicit its biological functions through three subtypes of endothelial differentiation gene (Edg) family G protein-coupled receptors (LPA1, LPA2 and LPA3) until our group identified a fourth subtype, LPA4. The discovery of this receptor, which is structurally distinct from the Edg family LPA receptors, led to the identification of two additional LPA receptors, LPA5 and LPA6, homologous to LPA4. These ‘non-Edg family’ LPA receptors now provide a new framework for understanding the diverse functions of LPA, including vascular development, platelet activation and hair growth. In this review, we summarize the identification, intracellular signalling and biological functions of this novel cluster of LPA receptors. Edg family LPA receptors, G protein-coupled receptor, lysophosphatidic acid, non-Edg family LPA receptors, orphan receptor Lysophosphatidic acid (LPA) is a simplest phospholipid consisting of a phosphate group, a glycerol moiety and a fatty acid. In spite of its simple structure, LPA exserts various biological functions and is involved in processes such as cell growth, differentiation, survival, motility and cytoskeletal changes (1). LPA is not a single molecular entity, and in fact, there are many LPA species (Fig. 1) (2). Either a saturated or unsaturated fatty acid is esterified at the sn-1 or sn-2 position of the glycerol backbone. In addition, the sn-1 alkyl or alkenyl ether-linked LPA species also exist. The biological activities of LPA depend on the length and the degree of unsaturation of the carbon chain attached to the glycerol backbone, as well as the type of linkage and its position. Fig. 1 View largeDownload slide Chemical structures of the molecular species of LPA. LPA contains an acyl- or ether-linked fatty acyl chain of various lengths and unsaturation levels. The acyl chain is esterified either at the sn-1 or sn-2 position of the glycerol backbone (1-acyl-LPA and 2-acyl-LPA, respectively), and the ether-linked LPAs carry an alkyl- or an alkenyl-linkage at the sn-1 position (alkyl-LPA and alkenyl-LPA, respectively). 1-Palmitoyl-LPA, 2-arachidonoyl-LPA and hexadecyl-LPA are shown as representative molecular species for 1-acyl-LPA, 2-acyl-LPA, and alkyl-LPA, respectively. Fig. 1 View largeDownload slide Chemical structures of the molecular species of LPA. LPA contains an acyl- or ether-linked fatty acyl chain of various lengths and unsaturation levels. The acyl chain is esterified either at the sn-1 or sn-2 position of the glycerol backbone (1-acyl-LPA and 2-acyl-LPA, respectively), and the ether-linked LPAs carry an alkyl- or an alkenyl-linkage at the sn-1 position (alkyl-LPA and alkenyl-LPA, respectively). 1-Palmitoyl-LPA, 2-arachidonoyl-LPA and hexadecyl-LPA are shown as representative molecular species for 1-acyl-LPA, 2-acyl-LPA, and alkyl-LPA, respectively. In 1960, Vogt (3) found that LPA induced the contraction of isolated rabbit duodenum preparations. To our knowledge, this is the first report of the biological activity of LPA. Subsequently, Tokumura et al. (4) reported vasopressor activities of several molecular species of LPA along with the relationship between their structure and activity. These pioneering works led to the disclosure of numerous bioactivities of LPA. However, because of experimental difficulties in its handling or its detergent-like property, questions remained about whether LPA serves as an agonist for LPA-specific receptors. Then, in 1989, Moolenaar and colleagues showed the GTP-dependency of LPA-induced phosphoinositide hydrolysis and the pertussis toxin (PTX) sensitivity of adenylyl cyclase inhibition (5). Subsequently, van der Bend et al. (6) reported strong evidence for the existence of a specific LPA-binding protein of 38–40 kDa using radiolabelled diazirine-LPA, a photoaffinity probe. These studies clearly proved the existence of a specific G protein-coupled receptor (GPCR) for LPA. Classic LPA Receptors (Edg family LPA Receptors) In 1990, Hla and colleagues found that one of the immediate early response genes cloned from human umbilical vein endothelial cells (HUVECs) encodes a rhodopsin family GPCR (7). They named it endothelial differentiation gene 1 (Edg1). Subsequently, several GPCRs that share substantial homology to Edg1 in their predicted amino acid sequences were cloned. These ‘Edg family’ GPCRs were considered to constitute a family of ‘orphan GPCRs’ whose ligands were yet to be identified. In 1996, Chun and colleagues demonstrated that overexpression of Edg2 in cultured neuronal cells resulted in enhanced morphological changes and adenylyl cyclase inhibition in response to LPA (8), providing the first evidence that a member of the Edg family GPCRs represented a functional receptor for LPA. This was quickly followed by the report by Hla and colleagues that Edg1 is a receptor for the related lysophospholipid, sphingosine-1-phosphate (9). Before 2000, reports from a number of research groups established that there are eight Edg receptor genes in the human genome, three of which encode LPA receptors and share 50–57% amino acid identity with each other: LPA1/Edg2 (8), LPA2/Edg4 (10), and LPA3/Edg7 (11,12). Edg family LPA receptors mediate intracellular Ca2+ mobilization, adenylyl cyclase inhibition and mitogen-activated protein kinase activation through PTX-sensitive and -insensitive G proteins. LPA1 and LPA2 couple with Gi, Gq and G12/13 proteins. Meanwhile, LPA3 couples with Gi and Gq proteins but not with G12/13 proteins. Knockout mice for these receptors have already been established. By analysing these mice, researchers have revealed important roles of Edg family LPA receptors in the nervous system (13–21), cancer progression (22), cardiovascular function (23), reproduction (24) and other processes (Table I). Details are discussed in a number of excellent reviews (1,25,26). Table I. Six subtypes of LPA receptors. Receptor  Aliases  Coupled G proteins  Phenotypes of knockout mice  LPA1  Edg2, vzg-1  Gi, Gq, G12/13  Craniofacial dysmorphism (13) Decreased post-natal growth rate (13) Increased apoptosis of Schwann cells in the sciatic nerve (13) Impaired suckling behaviour and partial neonatal lethality (13) Abnormal behaviours (15, 17, 20, 21) Increased adiposity (77) Abnormal cortical/neuronal development (18, 19) Resistance to neuropathic pain (16) Attenuated renal fibrosis (78) Attenuated pulmonary fibrosis (79)  LPA2  Edg4  Gi, Gq, G12/13  Increased radiation sensitivity of intestinal crypt (80) Attenuated injury-induced neointimal hyperplasia (LPA1/2-double knockout mice) (23) Attenuated tumourigenesis in the colon (22) Reduced allergic airway inflammation (81)  LPA3  Edg7  Gi, Gq  Delayed implantation (24) Altered embryo spacing (24)  LPA4  p2y9, GPR23  Gs, Gq, G12/13, (Gi)a  Increased bone density (39) Partial embryonic lethality with blood and lymphatic vessel malformation (44)  LPA5  GPR92, GPR93  Gq, G12/13  N/Ab  LPA6  p2y5  G12/13, (Gs), (Gi)  N/A  Receptor  Aliases  Coupled G proteins  Phenotypes of knockout mice  LPA1  Edg2, vzg-1  Gi, Gq, G12/13  Craniofacial dysmorphism (13) Decreased post-natal growth rate (13) Increased apoptosis of Schwann cells in the sciatic nerve (13) Impaired suckling behaviour and partial neonatal lethality (13) Abnormal behaviours (15, 17, 20, 21) Increased adiposity (77) Abnormal cortical/neuronal development (18, 19) Resistance to neuropathic pain (16) Attenuated renal fibrosis (78) Attenuated pulmonary fibrosis (79)  LPA2  Edg4  Gi, Gq, G12/13  Increased radiation sensitivity of intestinal crypt (80) Attenuated injury-induced neointimal hyperplasia (LPA1/2-double knockout mice) (23) Attenuated tumourigenesis in the colon (22) Reduced allergic airway inflammation (81)  LPA3  Edg7  Gi, Gq  Delayed implantation (24) Altered embryo spacing (24)  LPA4  p2y9, GPR23  Gs, Gq, G12/13, (Gi)a  Increased bone density (39) Partial embryonic lethality with blood and lymphatic vessel malformation (44)  LPA5  GPR92, GPR93  Gq, G12/13  N/Ab  LPA6  p2y5  G12/13, (Gs), (Gi)  N/A  aPreliminary data that require further confirmation are given in parentheses. bN/A, not applicable. View Large Non-Edg Family LPA Receptors Even after the identification of Edg family LPA receptors, there were several reports implying the existence of an additional LPA receptor(s). First, LPA-induced human platelet aggregation showed distinct ligand specificity, which was not accounted for by Edg family LPA receptor-mediated responses (27–29). Human platelets aggregated more potently in response to alkyl ether-linked LPA (alkyl-LPA) than to the corresponding ester-linked LPA (acyl-LPA). However, all Edg family LPA receptors prefer acyl-LPA to alkyl-LPA. Secondly, rat hepatoma RH7777 cells that do not express any of Edg family LPA receptors showed a mitogenic response to LPA and its analogs (30). Of note, the stereoselectivity of the response was similar to that of human platelets. Thirdly, in a study of fibroblasts from LPA1/LPA2 double-knockout mice, some LPA-induced intracellular responses, including inositol phosphate production, adenylyl cyclase inhibition and stress fiber formation, were still observed but at reduced levels (31). Importantly, LPA3 mRNA was not detected in these double-knockout fibroblasts. In 2003, we successfully identified the first non-Edg family LPA receptor, LPA4, in our attempt to de-orphanize the receptor p2y9/GPR23, which is structurally distant from the Edg family LPA receptors (32). As described below, our finding has led to identification of two additional LPA receptors, LPA5 and LPA6. These three receptors share 35–55% amino acid identity with each other and constitute a new family of LPA receptors, i.e., non-Edg family LPA receptors. From here, we extend our previous review (33) with the recent important findings on non-Edg family LPA receptors and their biological functions. LPA4 LPA4 (p2y9/GPR23) was cloned as an orphan GPCR and is closely related to the purinergic P2Y receptors (34,35) whereas, it shares only 20–24% amino acid identity with Edg family LPA receptors. As p2y9/GPR23 shows some homology with platelet-activating factor receptors and cysteinyl-leukotriene receptors (Fig. 2), we assumed that the orphan receptor might be activated by some lipid ligands. We screened 198 lipids with Chinese hamster ovary (CHO) cells stably transfected with p2y9/GPR23 and found that LPA induced both intracellular Ca2+ mobilization and cAMP formation through p2y9/GPR23 (32). Radioligand binding assays with membrane fractions of RH7777 cells transiently transfected with p2y9/GPR23, demonstrated specific binding of LPA to p2y9/GPR23. Scatchard analysis of the binding data gave a dissociation constant (Kd) of 44.8 nM, which is approximately equivalent to the Kd values of LPA with LPA1 and LPA2. Later, Lee et al. (36) confirmed p2y9/GPR23 as a fourth LPA receptor using mouse p2y9/GPR23 cDNA, and it is now generally accepted as LPA4 (37). Fig. 2 View largeDownload slide A representative phylogenetic tree of human GPCRs. Amino acid sequences of selected human GPCRs were obtained from GenBank and SwissProt and aligned using the program, ClustalW, distributed by DNA Data Bank of Japan (DDBJ) (http://clustalw.ddbj.nig.ac.jp/top-j.html). Phylogenetic tree was generated using the FigTree v1.3.1 program. Note that non-Edg family LPA receptors are located rather distantly from Edg family LPA receptors. Fig. 2 View largeDownload slide A representative phylogenetic tree of human GPCRs. Amino acid sequences of selected human GPCRs were obtained from GenBank and SwissProt and aligned using the program, ClustalW, distributed by DNA Data Bank of Japan (DDBJ) (http://clustalw.ddbj.nig.ac.jp/top-j.html). Phylogenetic tree was generated using the FigTree v1.3.1 program. Note that non-Edg family LPA receptors are located rather distantly from Edg family LPA receptors. Intracellular signalling of LPA4 As described above, LPA increased intracellular levels of Ca2+ and cAMP in CHO cells stably expressing LPA4 (CHO-LPA4 cells) (32). These observations suggest that LPA4 couples to both Gs and Gq proteins. Since PTX-treatment enhanced the LPA-induced increase of intracellular cAMP, its coupling to Gi protein also seemed possible. Lee et al. (36) confirmed that LPA4 couples to Gs, Gi, and Gq proteins using rat neuroblastoma B103 cells. They demonstrated that LPA-induced Ca2+ mobilization in B103-LPA4 cells was mediated by both Gq and Gi proteins. The increase of Gs-dependent intracellular cAMP levels from exposure to LPA was also shown in these cells. However, contrary to this study, LPA did not increase intracellular cAMP in B103-LPA4 cells from our laboratory (38). In addition, we found that LPA-induced Ca2+ mobilization in B103-LPA4 cells completely depends on Gq protein in an experiment with YM254890, a Gq-inhibitor. Although the reasons for the apparent discrepancy are still unknown, coupling efficiency of LPA4 to Gs or Gi protein may depend on the culture conditions or the receptor expression levels. The cell-type specificity of the coupling to Gs was observed for endogenously expressed LPA4 as well. In human mesenchymal stem cells (hMSCs) after osteogenic induction (39) and human fibrosarcoma HT1080 cells (40), the LPA–LPA4 interaction evoked Gs-dependent cellular functions. However, no increase in intracellular cAMP was observed in mouse embryonic fibroblasts (MEFs) (31), which express functional LPA4 receptors (41). Importantly, LPA4 couples to G12/13 proteins and activates Rho. We found that LPA4 mediates Rho-associated kinase (ROCK)-dependent neurite retraction and cell aggregation in B103-LPA4 cells (38). Consistently, Lee et al. (36) showed G12/13-dependent cytoskeletal changes of RH7777-LPA4 cells and B103-LPA4 cells. In the presence of serum, B103-LPA4 cells formed cell aggregates through activation of the G12/13-Rho-ROCK signalling axis (38). In sharp contrast with B103-LPA4 cells, B103-LPA1 cells exhibited a flattened morphology, which was likely evoked by the LPA1-Gi-Rac signalling axis (38, 42). It is interesting that inactivation of Gi protein in B103-LPA1 cells by PTX treatment led to formation of the aggregated morphology, as observed in B103-LPA4 cells (38). Given that Rho and Rac activities are mutually inhibitory (43), LPA1 and LPA4 may suppress the intracellular signalling to each other through Rac and Rho, respectively. The LPA4-G12/13-Rho pathway was also observed in MEFs (41). In MEFs from LPA4 knockout embryos, LPA-induced Rho activation was severely attenuated. Instead, they showed extremely enhanced LPA1-dependent Rac activation and chemotaxis. Biological functions of LPA4 To date, three independent research groups, including ours, have generated LPA4 knockout mice. Lee et al. (41) observed no obvious abnormality in their LPA4 knockout mice with a mixed 129/Sv and C57BL/6 genetic background. In another study, Liu et al. (39) showed increased trabecular bone density in LPA4 knockout mice. This study further demonstrated that the mRNA expression of LPA4 is extremely high in the hMSCs after osteogenic induction, and in the mouse tibia. Using siRNA against LPA4, LPA4 was shown to mediate the increase of intracellular cAMP level in hMSCs, which seems responsible for the inhibition of osteogenic differentiation. We generated LPA4 knockout mice with a pure C57BL/6 genetic background (44). In contrast to the previous two reports, our LPA4 knockout mice displayed reduced litter size compared with wild-type mice. The apparent discrepancy between previous reports and our study might be caused by strain differences and/or different experimental conditions. Subsequent analysis revealed that ∼30% of LPA4 knockout embryos did not survive gestation and displayed haemorrhages and/or oedema in many organs, including the heart, skin and lung. In LPA4 knockout embryos with bleeding, the blood vessels were dilated. Furthermore, the recruitments of smooth muscle cells and pericytes were impaired. The defects in blood vessel formation in LPA4 knockout mice were also observed in Matrigel plug assays using adult LPA4 knockout mice, which showed no obvious abnormalities. In the embryos with oedema, lymphatic vessels were also dilated. These data indicate an essential role of LPA4 in normal blood and lymphatic vessel development. Of note, the LPA producing enzyme autotaxin (ATX) has also been shown to have a key role in vascular development (45). All ATX knockout embryos died with severe vascular defects in the embryos (46–49). Interestingly, the phenotypes of G13 knockout mice were remarkably similar to those of ATX-knockout mice, which included impaired vascular development (50–52). These studies suggested that LPA produced by ATX has a critical role in vascular development through a G13-coupling LPA receptor(s). However, the responsible LPA receptor(s) had been unknown because none of the single or multiple knockout mice for LPA1, LPA2 or LPA3 showed such vascular anomalies (45). Currently, LPA4 seems to be one of the ‘missing links’ connecting ATX and G13. However, the phenotype observed in LPA4 knockout mice was partially penetrant, suggesting that other G13-coupling LPA receptor(s) is involved in the vascular development. Since five out of six LPA receptors couple to G12/13 proteins, multiple LPA receptors might have cooperative and redundant roles in this developmental process. LPA4 mRNA is abundant not only in embryos but also in ovary, uterus and placenta in mice (33). Whether LPA4 has some roles in female reproduction must await further analysis of LPA4 knockout mice. LPA5 (GPR92/93) In 2005, two independent research groups identified a fifth LPA receptor, LPA5 (GPR92/93). While Lee et al. (53) searched for an additional LPA receptor that affects actin cytoskeleton from collections of GPCR cDNAs, they observed a positive response in cells expressing GPR92/93, which was an orphan GPCR closely related to LPA4 with ∼35% amino acid identity. Independently, Kotarsky et al. (54) focused on serum as a source of an endogenous ligand for GPR92/93 that shows high expression in leukocyte cell lines. Using a reporter gene assay, they isolated a fraction from bovine serum that activated GPR92/93 and found that LPA bound to albumin is an agonist. Both reports showed specific bindings of radiolabelled LPA to membrane fractions from GPR92/93-overexpressing cells. The Kd value for GPR92/93 shown in the latter report was 6.4 nM, which is much lower than the Kd value (88.6 nM) which we obtained with RH7777 cell membranes transiently expressing GPR92/93 (55). Non-LPA agonists for LPA5 Although GPR92/93 was reported as a fifth LPA receptor, LPA5, there are several studies showing the existence of several non-LPA agonists for this receptor. Choi et al. (56) reported that peptone (protein hydrolysates) activated LPA5 in a dose-dependent manner with an EC50 of 10.6 mg/ml. They also showed the synergistic effect of peptone and LPA on the activation of LPA5. Oh et al. (57) reported that farnesyl pyrophosphate (FPP) at nM concentrations and N-arachidonoylglycine at µM concentrations showed potent agonist activities toward LPA5. In their study, FPP was a more potent agonist towards LPA5 than myristoyl-LPA. However, oleoyl-LPA showed higher activity than FPP in the report by Williams et al. (58). We also confirmed that oleoyl-LPA was a more potent activator of LPA5 than FPP (K.Y. and S.I., our unpublished data). Further analysis with knockout mice will be necessary to determine whether these non-LPA agonists for LPA5 actually function in vivo. Intracellular signalling of LPA5 LPA5 couples to Gq and G12/13 proteins (53). In B103-LPA5 cells, LPA increased intracellular Ca2+ and cAMP levels and induced Rho-dependent neurite retraction. Experiments with minigenes revealed the involvement of Gq protein in Ca2+ mobilization and of G12/13 proteins in neurite retraction. LPA5-dependent increase of intracellular cAMP was observed not only in B103-LPA5 cells but also in LPA5-overexpressing HeLa cells (54). However, a Gs minigene did not affect the LPA-induced cAMP production in B103-LPA5 cells, indicating that LPA5 mediates the activation of adenylyl cyclase in a Gs-independent manner (53). Biological functions of LPA5 Knockout mice with the Lpar5 gene deletion have not yet been reported. However, LPA5 mRNA is highly expressed in small intestine and stomach in mice (53,54,56). Consistently, LPA5 expressed in intestinal epithelial cells has been suggested to play an important role in LPA-induced fluid absorption in mice (59). In mouse small intestine, LPA5 is expressed not only in epithelial cells, but also in intraepithelial lymphocytes, which mainly consist of CD8+ cells (54). As LPA5 is also expressed in other immune cells and the spleen (53), some immunological functions of LPA5 are assumed. Very recently, Lundequist and Boyce (60) reported that human mast cells express LPA5 mRNA at a high level. LPA5-mediated LPA-induced release of macrophage inflammation protein-1β from these cells. Mouse dorsal root ganglion (DRG) was also shown to be rich in LPA5 mRNA (53,57). Oh et al. (57) demonstrated the existence of a functional LPA5 receptor in rat cultured DRG neurons. They observed LPA5-dependent Ca2+ mobilization in DRG neurons with small diameters but not in those with large diameters. The study reported that there were many DRG neurons double-positive for the presence of LPA5 and the nociceptor transient receptor potential vanilloid type 1. Thus, LPA5 may play a significant role in nociceptive transmission and pain perception. LPA directly induces human platelet aggregation. As discussed earlier, the LPA responses of platelets are inconsistent with the pharmacological properties of the classic Edg family LPA receptors, suggesting the existence of a ‘platelet-type’ LPA receptor(s) with a preference for alkyl-LPA over acyl-LPA (29). Notably, gene expression profiling of human platelets for GPCRs showed the highest expression of LPA5 among LPA receptors identified (61). In recent studies with LPA5-selective agonists, LPA5 was suggested to be the ‘platelet-type’ LPA receptor (58, 62). More recently, Khandoga et al. (63) showed that LPA-induced cell shape changes were abolished by siRNA against LPA5 in two human megakaryocytic cell lines (Dami and Meg-01). The rank order of activation by LPA species in these cells was similar to that of human platelets, supporting the idea that LPA5 corresponds to the ‘platelet-type’ LPA receptor. Importantly, LPA was identified as a main platelet-activating lipid of mildly oxidized low-density lipoprotein and human atherosclerotic lesions (64). Thus, LPA5 may be a novel target for anti-thrombotic therapy for patients with myocardial infarction and stroke. LPA6 (p2y5) LPA6 (p2y5) was originally an orphan receptor encoded in an intron of the retinoblastoma gene (65). The fact that p2y5 shares the highest sequence homology with p2y9/GPR23/LPA4 among all GPCRs strongly suggested that LPA is a ligand for p2y5. However, we could not detect LPA-induced Ca2+ mobilization or cAMP level changes in p2y5-overexpressing cells initially at the time of the identification of LPA4 (32). However, we noticed that B103-p2y5 cells formed aggregates when cultured with serum (55). As was described above, we previously showed that B103-LPA4 cells formed aggregates through the activation of Rho in serum-containing medium, which is abundant in LPA (38). Thus, the similar cell morphology between B103-p2y5 cells and B103-LPA4 cells implied activation of the p2y5-Rho signalling axis by LPA. By analysing RH7777-p2y5 and B103-p2y5 cells, we obtained consistent data that p2y5 actually responded to LPA with activation of the G12/13-Rho signalling pathway (discussed below) (55). Furthermore, membrane fractions of RH7777 cells stably expressing p2y5 displayed specific binding to radiolabelled LPA (55). During our analysis of p2y5 as a novel LPA receptor, two independent research groups reported that several mutations in the p2y5 gene underlie autosomal recessive hypotrichosis/woolly hair (66,67). It is noteworthy that membrane-bound phosphatidic acid-selective phospholipase A1α (mPA-PLA1α or LIPH), a 2-acyl-LPA-producing enzyme (68), is encoded by a causative gene for autosomal recessive hypotrichosis/woolly hair (69), which has clinical features quite similar to those caused by the p2y5 mutations. Based on this similarity, Pasternack et al. (66) showed LPA-dependent cAMP level changes and specific binding of radiolabelled LPA in p2y5-overexpressing cells and proposed that p2y5 is a LPA receptor. Lee et al. (70) independently confirmed that LPA is a ligand for p2y5 by biochemical analysis. They also showed the specific binding of radiolabelled LPA to membrane fractions from p2y5-overexpressing cells. p2y5 was recently designated as LPA6 by the International Union of Basic and Clinical Pharmacology Committee for LPA receptor nomenclature (37). Intracellular signalling of LPA6 Pasternack et al. (66) showed that LPA induced the increase of intracellular cAMP levels in CHO-LPA6 cells. However, in our research, no significant change in intracellular cAMP levels was detected by LPA in CHO, B103 and RH7777 cells overexpressing LPA6 (55). An independent study by Lee and colleagues (66) also showed no cAMP increase in CHO-LPA6 cells. Instead, they showed LPA-dependent inhibition of forskolin-triggered elevation of cAMP in CHO-LPA6 cells. The reason for these discrepancies is unknown. Since CHO cells have intrinsic responses to LPA, the confirmation with other cell lines would be necessary to elucidate the efficacy of its coupling to Gs and Gi proteins. While no LPA6-mediated changes of intracellular cAMP or Ca2+ levels were detected, we found that LPA rapidly induces neurite retraction in B103-LPA6 cells and membrane blebbing in RH7777-LPA6 cells (55). These morphological changes were Y27632-sensitive, indicating involvement of ROCK in the LPA6 signalling. When B103-LPA6 cells were transfected with Gs/13 protein, a chimeric α subunit of Gs and G13 proteins that enables G13-coupling GPCRs to activate adenylyl cyclases (71), LPA increased the cAMP level in a dose-dependent manner. The coupling of LPA6 to G13 protein was further confirmed by the examination of [35S]GTPγS incorporation into Gα13 protein by immunoprecipitation with anti-Gα13 protein antibody. Consistent with our results, Lee et al. (70) also demonstrated that LPA6 couples to G12/13 proteins. Biological functions of LPA6 Consistent with the involvement in human hair growth, LPA6 mRNA expression is localized in Huxley's layer of the hair follicle inner root sheath and the epidermis in humans (67). As mRNA of mPA-PLA1α shows similar expression distribution to that of LPA6 (72), mPA-PLA1α-derived 2-acyl-LPA is likely to act on LPA6 in an autocrine/paracrine manner (73). Indeed, we revealed that LPA6 shows ligand preference for 2-acyl-LPA over 1-acyl-LPA in heterologous expression experiments (55). Further studies are needed for understanding the precise mechanisms by which LPA regulates human hair growth, including responsible G proteins that function downstream of LPA6. It is interesting that the guanine nucleotide-binding protein subunit alpha-12 gene (GNA12) that encodes G12 protein was recently reported to be a strong candidate for the autosomal recessive transmission of hereditary hypotrichosis in a Pakistani family, although direct sequencing analysis of coding sequence failed to detect mutations (74). It has been reported that HUVECs show Rho-dependent actin reorganization in response to LPA (75,76). We detected high expression of LPA6 mRNA in HUVECs (55). Following siRNA-mediated knockdown of LPA6, remarkable inhibition of the LPA-induced HUVEC contraction was observed. Thus, endogenously expressed LPA6 in HUVECs is likely to play a major role in the Rho-mediated morphological changes induced by LPA, raising a possibility that LPA6 regulates vascular permeability as another of its physiological roles. LPA6 is also expressed in cells and tissues other than hair follicles and vascular epithelium (K.Y. and S.I., our unpublished data). Although no other defects including vascular dysfunction have been reported in hypotrichosis/woolly hair patients with the LPAR6 gene mutations, this LPA receptor may play important, yet overlooked, roles in some physiological and/or pathological situations. Conclusions In this review, we have discussed the recent studies on the identification, intracellular signalling and biological functions of non-Edg family LPA receptors, LPA4, LPA5 and LPA6. The discovery of these novel LPA receptors now provides a new framework for understanding pleiotropic functions of LPA. Recent studies have revealed physiological and pathological roles of these receptors, including vascular development, platelet activation and hair growth. However, much less is known about these receptors compared with the Edg family LPA receptors. Further studies, including those with knockout mice, will be necessary for further understanding of this novel cluster of LPA receptors. In addition, the development of pharmacological tools, including specific antagonists and agonists for these receptors, will not only help to reveal the physiological and pathological roles of the receptors but also lead to development of novel therapeutic strategies for various diseases. Funding Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, Sports, and Technology of Japan (to K.Y. and S.I.); Health and Labor Sciences Research Grant for the Research on Allergic Disease and Immunology from the Ministry of Health, Labor, and Welfare of Japan (to S.I.); a grant to the Respiratory Failure Research Group from the Ministry of Health, Labor, and Welfare of Japan (to S.I.); grants from the Takeda Science Foundation; the Naito Foundation; the Mochida Memorial Foundation and the Uehara Memorial Foundation (to S.I.). Conflict of interest None declared. Acknowledgements The authors thank Professor Takao Shimizu (Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo) and all his lab members. Abbreviations Abbreviations acyl-LPA ester-linked LPA alkyl-LPA alkyl ether-linked LPA ATX autotaxin CHO Chinese hamster ovary DRG dorsal root ganglion Edg endothelial differentiation gene FPP farnesyl pyrophosphate GPCR G protein-coupled receptor hMSC human mesenchymal stem cell HUVEC human umbilical vein endothelial cell Kd dissociation constant LPA lysophosphatidic acid MEF mouse embryonic fibroblast mPA-PLA1α membrane bound phosphatidic acid-selective phospholipase A1α PTX pertussis toxin ROCK Rho-associated kinase References 1 Choi JW,  Herr DR,  Noguchi K,  Yung YC,  Lee CW,  Mutoh T,  Lin ME,  Teo ST,  Park KE,  Mosley AN,  Chun J.  LPA receptors: subtypes and biological actions,  Annu. Rev. Pharmacol. Toxicol. ,  2010, vol.  50 (pg.  157- 186) Google Scholar CrossRef Search ADS PubMed  2 Tokumura A.  A family of phospholipid autacoids: occurrence, metabolism and bioactions,  Prog. Lipid. Res. ,  1995, vol.  34 (pg.  151- 184) Google Scholar CrossRef Search ADS PubMed  3 Vogt W.  Intestine-stimulating activity of various phosphatides and glycolipids. Naunyn Schmiedebergs Arch. Exp,  Pathol. Pharmakol. ,  1960, vol.  240 (pg.  134- 139) 4 Tokumura A,  Fukuzawa K,  Tsukatani H.  Effects of synthetic and natural lysophosphatidic acids on the arterial blood pressure of different animal species,  Lipids ,  1978, vol.  13 (pg.  572- 574) Google Scholar CrossRef Search ADS PubMed  5 van Corven EJ,  Groenink A,  Jalink K,  Eichholtz T,  Moolenaar WH.  Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins,  Cell ,  1989, vol.  59 (pg.  45- 54) Google Scholar CrossRef Search ADS PubMed  6 van der Bend RL,  Brunner J,  Jalink K,  van Corven EJ,  Moolenaar WH,  van Blitterswijk WJ.  Identification of a putative membrane receptor for the bioactive phospholipid, lysophosphatidic acid,  EMBO J. ,  1992, vol.  11 (pg.  2495- 2501) Google Scholar PubMed  7 Hla T,  Maciag T.  An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors,  J. Biol. Chem. ,  1990, vol.  265 (pg.  9308- 9313) Google Scholar PubMed  8 Hecht JH,  Weiner JA,  Post SR,  Chun J.  Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex,  J. Cell Biol ,  1996, vol.  135 (pg.  1071- 1083) Google Scholar CrossRef Search ADS PubMed  9 Lee MJ,  Van Brocklyn JR,  Thangada S,  Liu CH,  Hand AR,  Menzeleev R,  Spiegel S,  Hla T.  Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1,  Science ,  1998, vol.  279 (pg.  1552- 1555) Google Scholar CrossRef Search ADS PubMed  10 An S,  Bleu T,  Hallmark OG,  Goetzl EJ.  Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid,  J. Biol. Chem. ,  1998, vol.  273 (pg.  7906- 7910) Google Scholar CrossRef Search ADS PubMed  11 Bandoh K,  Aoki J,  Hosono H,  Kobayashi S,  Kobayashi T,  Murakami-Murofushi K,  Tsujimoto M,  Arai H,  Inoue K.  Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid,  J. Biol. Chem. ,  1999, vol.  274 (pg.  27776- 27785) Google Scholar CrossRef Search ADS PubMed  12 Im DS,  Heise CE,  Harding MA,  George SR,  O'Dowd BF,  Theodorescu D,  Lynch KR.  Molecular cloning and characterization of a lysophosphatidic acid receptor, Edg-7, expressed in prostate,  Mol. Pharmacol. ,  2000, vol.  57 (pg.  753- 759) Google Scholar PubMed  13 Contos JJ,  Fukushima N,  Weiner JA,  Kaushal D,  Chun J.  Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior,  Proc. Natl Acad. Sci. USA ,  2000, vol.  97 (pg.  13384- 13389) Google Scholar CrossRef Search ADS   14 Kingsbury MA,  Rehen SK,  Contos JJ,  Higgins CM,  Chun J.  Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding,  Nat. Neurosci. ,  2003, vol.  6 (pg.  1292- 1299) Google Scholar CrossRef Search ADS PubMed  15 Harrison SM,  Reavill C,  Brown G,  Brown JT,  Cluderay JE,  Crook B,  Davies CH,  Dawson LA,  Grau E,  Heidbreder C,  Hemmati P,  Hervieu G,  Howarth A,  Hughes ZA,  Hunter AJ,  Latcham J,  Pickering S,  Pugh P,  Rogers DC,  Shilliam CS,  Maycox PR.  LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease,  Mol. Cell. Neurosci. ,  2003, vol.  24 (pg.  1170- 1179) Google Scholar CrossRef Search ADS PubMed  16 Inoue M,  Rashid MH,  Fujita R,  Contos JJ,  Chun J,  Ueda H.  Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling,  Nat. Med. ,  2004, vol.  10 (pg.  712- 718) Google Scholar CrossRef Search ADS PubMed  17 Cunningham MO,  Hunt J,  Middleton S,  LeBeau FE,  Gillies MJ,  Davies CH,  Maycox PR,  Whittington MA,  Racca C.  Region-specific reduction in entorhinal gamma oscillations and parvalbumin-immunoreactive neurons in animal models of psychiatric illness,  J. Neurosci. ,  2006, vol.  26 (pg.  2767- 2776) Google Scholar CrossRef Search ADS PubMed  18 Estivill-Torrus G,  Llebrez-Zayas P,  Matas-Rico E,  Santin L,  Pedraza C,  De Diego I,  Del Arco I,  Fernandez-Llebrez P,  Chun J,  De Fonseca FR.  Absence of LPA1 signaling results in defective cortical development,  Cereb. Cortex ,  2008, vol.  18 (pg.  938- 950) Google Scholar CrossRef Search ADS PubMed  19 Matas-Rico E,  Garcia-Diaz B,  Llebrez-Zayas P,  Lopez-Barroso D,  Santin L,  Pedraza C,  Smith-Fernandez A,  Fernandez-Llebrez P,  Tellez T,  Redondo M,  Chun J,  De Fonseca FR,  Estivill-Torrus G.  Deletion of lysophosphatidic acid receptor LPA1 reduces neurogenesis in the mouse dentate gyrus,  Mol. Cell. Neurosci. ,  2008, vol.  39 (pg.  342- 355) Google Scholar CrossRef Search ADS PubMed  20 Santin LJ,  Bilbao A,  Pedraza C,  Matas-Rico E,  Lopez-Barroso D,  Castilla-Ortega E,  Sanchez-Lopez J,  Riquelme R,  Varela-Nieto I,  de la Villa P,  Suardiaz M,  Chun J,  De Fonseca FR,  Estivill-Torrus G.  Behavioral phenotype of maLPA1-null mice: increased anxiety-like behavior and spatial memory deficits,  Genes Brain Behav. ,  2009, vol.  8 (pg.  772- 784) Google Scholar CrossRef Search ADS PubMed  21 Castilla-Ortega E,  Sanchez-Lopez J,  Hoyo-Becerra C,  Matas-Rico E,  Zambrana-Infantes E,  Chun J,  De Fonseca FR,  Pedraza C,  Estivill-Torrus G,  Santin LJ.  Exploratory, anxiety and spatial memory impairments are dissociated in mice lacking the LPA1 receptor,  Neurobiol. Learn. Mem. ,  2010, vol.  94 (pg.  73- 82) Google Scholar CrossRef Search ADS PubMed  22 Lin S,  Wang D,  Iyer S,  Ghaleb AM,  Shim H,  Yang VW,  Chun J,  Yun CC.  The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer,  Gastroenterology ,  2009, vol.  136 (pg.  1711- 1720) Google Scholar CrossRef Search ADS PubMed  23 Panchatcharam M,  Miriyala S,  Yang F,  Rojas M,  End C,  Vallant C,  Dong A,  Lynch K,  Chun J,  Morris AJ,  Smyth SS.  Lysophosphatidic acid receptors 1 and 2 play roles in regulation of vascular injury responses but not blood pressure,  Circ. Res. ,  2008, vol.  103 (pg.  662- 670) Google Scholar CrossRef Search ADS PubMed  24 Ye X,  Hama K,  Contos JJ,  Anliker B,  Inoue A,  Skinner MK,  Suzuki H,  Amano T,  Kennedy G,  Arai H,  Aoki J,  Chun J.  LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing,  Nature ,  2005, vol.  435 (pg.  104- 108) Google Scholar CrossRef Search ADS PubMed  25 Choi JW,  Lee CW,  Chun J.  Biological roles of lysophospholipid receptors revealed by genetic null mice: an update,  Biochim. Biophys. Acta. ,  2008, vol.  1781 (pg.  531- 539) Google Scholar CrossRef Search ADS PubMed  26 Noguchi K,  Herr D,  Mutoh T,  Chun J.  Lysophosphatidic acid (LPA) and its receptors,  Curr. Opin. Pharmacol. ,  2009, vol.  9 (pg.  15- 23) Google Scholar CrossRef Search ADS PubMed  27 Simon MF,  Chap H,  Douste-Blazy L.  Human platelet aggregation induced by 1-alkyl-lysophosphatidic acid and its analogs: a new group of phospholipid mediators?,  Biochem. Biophys. Res. Commun. ,  1982, vol.  108 (pg.  1743- 1750) Google Scholar CrossRef Search ADS PubMed  28 Gueguen G,  Gaige B,  Grevy JM,  Rogalle P,  Bellan J,  Wilson M,  Klaebe A,  Pont F,  Simon MF,  Chap H.  Structure-activity analysis of the effects of lysophosphatidic acid on platelet aggregation,  Biochemistry ,  1999, vol.  38 (pg.  8440- 8450) Google Scholar CrossRef Search ADS PubMed  29 Tokumura A,  Sinomiya J,  Kishimoto S,  Tanaka T,  Kogure K,  Sugiura T,  Satouchi K,  Waku K,  Fukuzawa K.  Human platelets respond differentially to lysophosphatidic acids having a highly unsaturated fatty acyl group and alkyl ether-linked lysophosphatidic acids,  Biochem. J. ,  2002, vol.  365 (pg.  617- 628) Google Scholar CrossRef Search ADS PubMed  30 Hooks SB,  Santos WL,  Im DS,  Heise CE,  Macdonald TL,  Lynch KR.  Lysophosphatidic acid-induced mitogenesis is regulated by lipid phosphate phosphatases and is Edg-receptor independent,  J. Biol. Chem. ,  2001, vol.  276 (pg.  4611- 4621) Google Scholar CrossRef Search ADS PubMed  31 Contos JJ,  Ishii I,  Fukushima N,  Kingsbury MA,  Ye X,  Kawamura S,  Brown JH,  Chun J.  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. ,  2002, vol.  22 (pg.  6921- 6929) Google Scholar CrossRef Search ADS PubMed  32 Noguchi K,  Ishii S,  Shimizu T.  Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family,  J. Biol. Chem. ,  2003, vol.  278 (pg.  25600- 25606) Google Scholar CrossRef Search ADS PubMed  33 Ishii S,  Noguchi K,  Yanagida K.  Non-Edg family lysophosphatidic acid (LPA) receptors,  Prostaglandins Other Lipid Mediat. ,  2009, vol.  89 (pg.  57- 65) Google Scholar CrossRef Search ADS PubMed  34 O'Dowd BF,  Nguyen T,  Jung BP,  Marchese A,  Cheng R,  Heng HH,  Kolakowski LFJr.,  Lynch KR,  George SR.  Cloning and chromosomal mapping of four putative novel human G-protein-coupled receptor genes,  Gene ,  1997, vol.  187 (pg.  75- 81) Google Scholar CrossRef Search ADS PubMed  35 Janssens R,  Boeynaems JM,  Godart M,  Communi D.  Cloning of a human heptahelical receptor closely related to the P2Y5 receptor,  Biochem. Biophys. Res. Commun. ,  1997, vol.  236 (pg.  106- 112) Google Scholar CrossRef Search ADS PubMed  36 Lee CW,  Rivera R,  Dubin AE,  Chun J.  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. ,  2007, vol.  282 (pg.  4310- 4317) Google Scholar CrossRef Search ADS PubMed  37 Chun J,  Hla T,  Lynch KR,  Spiegel S,  Moolenaar WH.  International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature,  Pharmacol. Rev. ,  2011, vol.  62 (pg.  579- 587) Google Scholar CrossRef Search ADS   38 Yanagida K,  Ishii S,  Hamano F,  Noguchi K,  Shimizu T.  LPA4/p2y9/GPR23 mediates rho-dependent morphological changes in a rat neuronal cell line,  J. Biol. Chem. ,  2007, vol.  282 (pg.  5814- 5824) Google Scholar CrossRef Search ADS PubMed  39 Liu YB,  Kharode Y,  Bodine PV,  Yaworsky PJ,  Robinson JA,  Billiard J.  LPA induces osteoblast differentiation through interplay of two receptors: LPA1 and LPA4,  J. Cell. Biochem. ,  2010, vol.  109 (pg.  794- 800) Google Scholar PubMed  40 Harper K,  Arsenault D,  Boulay-Jean S,  Lauzier A,  Lucien F,  Dubois CM.  Autotaxin promotes cancer invasion via the lysophosphatidic acid receptor 4: participation of the cyclic AMP/EPAC/Rac1 signaling pathway in invadopodia formation,  Cancer Res. ,  2010, vol.  70 (pg.  4634- 4643) Google Scholar CrossRef Search ADS PubMed  41 Lee Z,  Cheng CT,  Zhang H,  Subler MA,  Wu J,  Mukherjee A,  Windle JJ,  Chen CK,  Fang X.  Role of LPA4/p2y9/GPR23 in negative regulation of cell motility,  Mol. Biol. Cell ,  2008, vol.  19 (pg.  5435- 5445) Google Scholar CrossRef Search ADS PubMed  42 van Leeuwen FN,  Olivo C,  Grivell S,  Giepmans BN,  Collard JG,  Moolenaar WH.  Rac activation by lysophosphatidic acid LPA1 receptors through the guanine nucleotide exchange factor Tiam1,  J. Biol. Chem. ,  2003, vol.  278 (pg.  400- 406) Google Scholar CrossRef Search ADS PubMed  43 Rottner K,  Hall A,  Small JV.  Interplay between Rac and Rho in the control of substrate contact dynamics,  Curr. Biol. ,  1999, vol.  9 (pg.  640- 648) Google Scholar CrossRef Search ADS PubMed  44 Sumida H,  Noguchi K,  Kihara Y,  Abe M,  Yanagida K,  Hamano F,  Sato S,  Tamaki K,  Morishita Y,  Kano MR,  Iwata C,  Miyazono K,  Sakimura K,  Shimizu T,  Ishii S.  LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis,  Blood ,  2010, vol.  116 (pg.  5060- 5070) Google Scholar CrossRef Search ADS PubMed  45 Nakanaga K,  Hama K,  Aoki J.  Autotaxin–an LPA producing enzyme with diverse functions,  J. Biochem. ,  2010, vol.  148 (pg.  13- 24) Google Scholar CrossRef Search ADS PubMed  46 van Meeteren LA,  Ruurs P,  Stortelers C,  Bouwman P,  van Rooijen MA,  Pradere JP,  Pettit TR,  Wakelam MJ,  Saulnier-Blache JS,  Mummery CL,  Moolenaar WH,  Jonkers J.  Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development,  Mol. Cell. Biol. ,  2006, vol.  26 (pg.  5015- 5022) Google Scholar CrossRef Search ADS PubMed  47 Tanaka M,  Okudaira S,  Kishi Y,  Ohkawa R,  Iseki S,  Ota M,  Noji S,  Yatomi Y,  Aoki J,  Arai H.  Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid,  J. Biol. Chem. ,  2006, vol.  281 (pg.  25822- 25830) Google Scholar CrossRef Search ADS PubMed  48 Koike S,  Keino-Masu K,  Ohto T,  Sugiyama F,  Takahashi S,  Masu M.  Autotaxin/lysophospholipase D-mediated lysophosphatidic acid signaling is required to form distinctive large lysosomes in the visceral endoderm cells of the mouse yolk sac,  J. Biol. Chem. ,  2009, vol.  284 (pg.  33561- 33570) Google Scholar CrossRef Search ADS PubMed  49 Fotopoulou S,  Oikonomou N,  Grigorieva E,  Nikitopoulou I,  Paparountas T,  Thanassopoulou A,  Zhao Z,  Xu Y,  Kontoyiannis DL,  Remboutsika E,  Aidinis V.  ATX expression and LPA signalling are vital for the development of the nervous system,  Dev. Biol. ,  2010, vol.  339 (pg.  451- 464) Google Scholar CrossRef Search ADS PubMed  50 Offermanns S,  Mancino V,  Revel JP,  Simon MI.  Vascular system defects and impaired cell chemokinesis as a result of Galpha13 deficiency,  Science ,  1997, vol.  275 (pg.  533- 536) Google Scholar CrossRef Search ADS PubMed  51 Gu JL,  Muller S,  Mancino V,  Offermanns S,  Simon MI.  Interaction of G alpha(12) with G alpha(13) and G alpha(q) signaling pathways,  Proc. Natl Acad. Sci. USA ,  2002, vol.  99 (pg.  9352- 9357) Google Scholar CrossRef Search ADS   52 Ruppel KM,  Willison D,  Kataoka H,  Wang A,  Zheng YW,  Cornelissen I,  Yin L,  Xu SM,  Coughlin SR.  Essential role for Galpha13 in endothelial cells during embryonic development,  Proc. Natl Acad. Sci. USA ,  2005, vol.  102 (pg.  8281- 8286) Google Scholar CrossRef Search ADS   53 Lee CW,  Rivera R,  Gardell S,  Dubin AE,  Chun J.  GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5,  J. Biol. Chem. ,  2006, vol.  281 (pg.  23589- 23597) Google Scholar CrossRef Search ADS PubMed  54 Kotarsky K,  Boketoft A,  Bristulf J,  Nilsson NE,  Norberg A,  Hansson S,  Owman C,  Sillard R,  Leeb-Lundberg LM,  Olde B.  Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes,  J. Pharmacol. Exp. Ther. ,  2006, vol.  318 (pg.  619- 628) Google Scholar CrossRef Search ADS PubMed  55 Yanagida K,  Masago K,  Nakanishi H,  Kihara Y,  Hamano F,  Tajima Y,  Taguchi R,  Shimizu T,  Ishii S.  Identification and characterization of a novel lysophosphatidic acid receptor, p2y5/LPA6,  J. Biol. Chem. ,  2009, vol.  284 (pg.  17731- 17741) Google Scholar CrossRef Search ADS PubMed  56 Choi S,  Lee M,  Shiu AL,  Yo SJ,  Aponte GW.  Identification of a protein hydrolysate responsive G protein-coupled receptor in enterocytes,  Am. J. Physiol. Gastrointest. Liver Physiol. ,  2007, vol.  292 (pg.  G98- G112) Google Scholar CrossRef Search ADS PubMed  57 Oh DY,  Yoon JM,  Moon MJ,  Hwang JI,  Choe H,  Lee JY,  Kim JI,  Kim S,  Rhim H,  O'Dell DK,  Walker JM,  Na HS,  Lee MG,  Kwon HB,  Kim K,  Seong JY.  Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92,  J. Biol. Chem. ,  2008, vol.  283 (pg.  21054- 21064) Google Scholar CrossRef Search ADS PubMed  58 Williams JR,  Khandoga AL,  Goyal P,  Fells JI,  Perygin DH,  Siess W,  Parrill AL,  Tigyi G,  Fujiwara Y.  Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation,  J. Biol. Chem. ,  2009, vol.  284 (pg.  17304- 17319) Google Scholar CrossRef Search ADS PubMed  59 Lin S,  Yeruva S,  He P,  Singh AK,  Zhang H,  Chen M,  Lamprecht G,  de Jonge HR,  Tse M,  Donowitz M,  Hogema BM,  Chun J,  Seidler U,  Yun CC.  Lysophosphatidic acid stimulates the intestinal brush border Na(+)/H(+) exchanger 3 and fluid absorption via LPA(5) and NHERF2,  Gastroenterology ,  2010, vol.  138 (pg.  649- 658) Google Scholar CrossRef Search ADS PubMed  60 Lundequist A,  Boyce JA.  LPA5 is abundantly expressed by human mast cells and important for lysophosphatidic acid induced MIP-1beta release,  PLoS ONE ,  2011, vol.  6 pg.  e18192  Google Scholar CrossRef Search ADS PubMed  61 Amisten S,  Braun OO,  Bengtsson A,  Erlinge D.  Gene expression profiling for the identification of G-protein coupled receptors in human platelets,  Thromb. Res. ,  2008, vol.  122 (pg.  47- 57) Google Scholar CrossRef Search ADS PubMed  62 Khandoga AL,  Fujiwara Y,  Goyal P,  Pandey D,  Tsukahara R,  Bolen A,  Guo H,  Wilke N,  Liu J,  Valentine WJ,  Durgam GG,  Miller DD,  Jiang G,  Prestwich GD,  Tigyi G,  Siess W.  Lysophosphatidic acid-induced platelet shape change revealed through LPA(1-5) receptor-selective probes and albumin,  Platelets ,  2008, vol.  19 (pg.  415- 427) Google Scholar CrossRef Search ADS PubMed  63 Khandoga AL,  Pandey D,  Welsch U,  Brandl R,  Siess W.  GPR92/LPA5 lysophosphatidate receptor mediates megakaryocytic cell shape change induced by human atherosclerotic plaques,  Cardiovasc. Res. ,  2011, vol.  90 (pg.  157- 164) Google Scholar CrossRef Search ADS PubMed  64 Siess W,  Zangl KJ,  Essler M,  Bauer M,  Brandl R,  Corrinth C,  Bittman R,  Tigyi G,  Aepfelbacher M.  Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions,  Proc. Natl Acad. Sci. USA ,  1999, vol.  96 (pg.  6931- 6936) Google Scholar CrossRef Search ADS   65 Herzog H,  Darby K,  Hort YJ,  Shine J.  Intron 17 of the human retinoblastoma susceptibility gene encodes an actively transcribed G protein-coupled receptor gene,  Genome Res. ,  1996, vol.  6 (pg.  858- 861) Google Scholar CrossRef Search ADS PubMed  66 Pasternack SM,  von Kugelgen I,  Aboud KA,  Lee YA,  Ruschendorf F,  Voss K,  Hillmer AM,  Molderings GJ,  Franz T,  Ramirez A,  Nurnberg P,  Nothen MM,  Betz RC.  G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth,  Nat. Genet. ,  2008, vol.  40 (pg.  329- 334) Google Scholar CrossRef Search ADS PubMed  67 Shimomura Y,  Wajid M,  Ishii Y,  Shapiro L,  Petukhova L,  Gordon D,  Christiano AM.  Disruption of P2RY5, an orphan G protein-coupled receptor, underlies autosomal recessive woolly hair,  Nat. Genet. ,  2008, vol.  40 (pg.  335- 339) Google Scholar CrossRef Search ADS PubMed  68 Sonoda H,  Aoki J,  Hiramatsu T,  Ishida M,  Bandoh K,  Nagai Y,  Taguchi R,  Inoue K,  Arai H.  A novel phosphatidic acid-selective phospholipase A1 that produces lysophosphatidic acid,  J. Biol. Chem. ,  2002, vol.  277 (pg.  34254- 34263) Google Scholar CrossRef Search ADS PubMed  69 Kazantseva A,  Goltsov A,  Zinchenko R,  Grigorenko AP,  Abrukova AV,  Moliaka YK,  Kirillov AG,  Guo Z,  Lyle S,  Ginter EK,  Rogaev EI.  Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH,  Science ,  2006, vol.  314 (pg.  982- 985) Google Scholar CrossRef Search ADS PubMed  70 Lee M,  Choi S,  Hallden G,  Yo SJ,  Schichnes D,  Aponte GW.  P2Y5 is a G(alpha)i, G(alpha)12/13 G protein-coupled receptor activated by lysophosphatidic acid that reduces intestinal cell adhesion,  Am. J. Physiol. Gastrointest. Liver Physiol. ,  2009, vol.  297 (pg.  G641- 654) Google Scholar CrossRef Search ADS PubMed  71 Hsu SH,  Luo CW.  Molecular dissection of G protein preference using Gsalpha chimeras reveals novel ligand signaling of GPCRs,  Am. J. Physiol. Endocrinol. Metab. ,  2007, vol.  293 (pg.  E1021- E1029) Google Scholar CrossRef Search ADS PubMed  72 Shimomura Y,  Wajid M,  Petukhova L,  Shapiro L,  Christiano AM.  Mutations in the Lipase H Gene Underlie Autosomal Recessive Woolly Hair/Hypotrichosis,  J. Invest. Dermatol. ,  2008, vol.  129 (pg.  622- 628) Google Scholar CrossRef Search ADS PubMed  73 Aoki J,  Inoue A,  Okudaira S.  Two pathways for lysophosphatidic acid production,  Biochim. Biophys. Acta. ,  2008, vol.  1781 (pg.  513- 518) Google Scholar CrossRef Search ADS PubMed  74 Basit S,  Ali G,  Wasif N,  Ansar M,  Ahmad W.  Genetic mapping of a novel hypotrichosis locus to chromosome 7p21.3-p22.3 in a Pakistani family and screening of the candidate genes,  Hum. Genet. ,  2010, vol.  128 (pg.  213- 220) Google Scholar CrossRef Search ADS PubMed  75 van Nieuw Amerongen GP,  Vermeer MA,  van Hinsbergh VW.  Role of RhoA and Rho kinase in lysophosphatidic acid-induced endothelial barrier dysfunction,  Arterioscler. Thromb. Vasc. Biol. ,  2000, vol.  20 (pg.  E127- E133) Google Scholar CrossRef Search ADS PubMed  76 Hirakawa M,  Oike M,  Karashima Y,  Ito Y.  Sequential activation of RhoA and FAK/paxillin leads to ATP release and actin reorganization in human endothelium,  J. Physiol. ,  2004, vol.  558 (pg.  479- 488) Google Scholar CrossRef Search ADS PubMed  77 Simon MF,  Daviaud D,  Pradere JP,  Gres S,  Guigne C,  Wabitsch M,  Chun J,  Valet P,  Saulnier-Blache JS.  Lysophosphatidic acid inhibits adipocyte differentiation via lysophosphatidic acid 1 receptor-dependent down-regulation of peroxisome proliferator-activated receptor gamma2,  J. Biol. Chem. ,  2005, vol.  280 (pg.  14656- 14662) Google Scholar CrossRef Search ADS PubMed  78 Pradere JP,  Klein J,  Gres S,  Guigne C,  Neau E,  Valet P,  Calise D,  Chun J,  Bascands JL,  Saulnier-Blache JS,  Schanstra JP.  LPA1 receptor activation promotes renal interstitial fibrosis,  J. Am. Soc. Nephrol. ,  2007, vol.  18 (pg.  3110- 3118) Google Scholar CrossRef Search ADS PubMed  79 Tager AM,  LaCamera P,  Shea BS,  Campanella GS,  Selman M,  Zhao Z,  Polosukhin V,  Wain J,  Karimi-Shah BA,  Kim ND,  Hart WK,  Pardo A,  Blackwell TS,  Xu Y,  Chun J,  Luster AD.  The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak,  Nat. Med. ,  2008, vol.  14 (pg.  45- 54) Google Scholar CrossRef Search ADS PubMed  80 Deng W,  Shuyu E,  Tsukahara R,  Valentine WJ,  Durgam G,  Gududuru V,  Balazs L,  Manickam V,  Arsura M,  VanMiddlesworth L,  Johnson LR,  Parrill AL,  Miller DD,  Tigyi G.  The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury,  Gastroenterology ,  2007, vol.  132 (pg.  1834- 1851) Google Scholar CrossRef Search ADS PubMed  81 Zhao Y,  Tong J,  He D,  Pendyala S,  Evgeny B,  Chun J,  Sperling AI,  Natarajan V.  Role of lysophosphatidic acid receptor LPA2 in the development of allergic airway inflammation in a murine model of asthma,  Respir. Res. ,  2009, vol.  10 pg.  114  Google Scholar CrossRef Search ADS PubMed  © The Authors 2011. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved
TI - Non-Edg family LPA receptors: the cutting edge of LPA research
JO - The Journal of Biochemistry
DO - 10.1093/jb/mvr087
DA - 2011-07-11
UR - https://www.deepdyve.com/lp/oxford-university-press/non-edg-family-lpa-receptors-the-cutting-edge-of-lpa-research-B6t00wZGdR
SP - 223
EP - 232
VL - 150
IS - 3
DP - DeepDyve
ER -