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Novel lysophosphoplipid receptors: their structure and function

Open AccessPublished:June 02, 2014DOI:https://doi.org/10.1194/jlr.R046920
      It is now accepted that lysophospholipids (LysoGPs) have a wide variety of functions as lipid mediators that are exerted through G protein-coupled receptors (GPCRs) specific to each lysophospholipid. While the roles of some LysoGPs, such as lysophosphatidic acid and sphingosine 1-phosphate, have been thoroughly examined, little is known about the roles of several other LysoGPs, such as lysophosphatidylserine (LysoPS), lysophosphatidylthreonine, lysophosphatidylethanolamine, lysophosphatidylinositol (LPI), and lysophosphatidylglycerol. Recently, a GPCR was found for LPI (GPR55) and three GPCRs (GPR34/LPS1, P2Y10/LPS2, and GPR174/LPS3) were found for LysoPS. In this review, we focus on these newly identified GPCRs and summarize the actions of LysoPS and LPI as lipid mediators.
      Lysophospholipids (LysoGPs) (1-acyl-2-LPL or 2-acyl-1-LPL) are deacylated forms of phospholipids with a single fatty acid chain and are produced by either phospholipase A (PLA)1 or PLA2 (
      • Aoki J.
      Mechanisms of lysophosphatidic acid production.
      ,
      • Makide K.
      • Kitamura H.
      • Sato Y.
      • Okutani M.
      • Aoki J.
      Emerging lysophospholipid mediators, lysophosphatidylserine, lyso­phos­phatidylthreonine, lysophosphatidylethanolamine and lysophosphatidylglycerol.
      ). Various LysoGPs have been detected in biological samples such as plasma, including lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), lysophosphatidylethanolamine (LPE), lysophosphatidylserine (LysoPS), lysophosphatidylinositol (LPI), lysophosphatidylglycerol (LPG), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC) (Fig. 1). These LysoGPs serve as precursors of diacyl phospholipids and at least some of them are also lipid mediators. LPA and S1P (Fig. 1) are lysophospholipid mediators with plasma concentrations of 10–30 nM and several hundred nanomoles, respectively (
      • Aoki J.
      • Inoue A.
      • Okudaira S.
      Two pathways for lysophosphatidic acid production.
      ,
      • Fukuhara S.
      • Simmons S.
      • Kawamura S.
      • Inoue A.
      • Orba Y.
      • Tokudome T.
      • Sunden Y.
      • Arai Y.
      • Moriwaki K.
      • Ishida J.
      • et al.
      The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice.
      ). Both LPA and S1P have critical roles in multiple cellular events through G protein-coupled receptors (GPCRs). Six GPCRs have been identified for LPA (LPA1–6) and five GPCRs have been identified for S1P (S1P1–5) (
      • Chun J.
      • Hla T.
      • Lynch K.R.
      • Spiegel S.
      • Moolenaar W.H.
      International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature.
      ), and nomenclature of these LysoGPs receptors has recently been proposed by Kihara et al. (

      KiharaY.MaceykaM.SpiegelS.ChunJ.. Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br. J. Pharmacol., 171: 3575–3594.

      ). These receptors are grouped into two classes, the Edg and P2Y families, respectively. LPA1–3 and all five of the S1P receptors, S1P1–5, are members of the Edg family, while LPA4–6 are members of the P2Y family. In addition, LPA is an endogenous ligand for PPARγ (
      • McIntyre T.M.
      • Pontsler A.V.
      • Silva A.R.
      • St Hilaire A.
      • Xu Y.
      • Hinshaw J.C.
      • Zimmerman G.A.
      • Hama K.
      • Aoki J.
      • Arai H.
      • et al.
      Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARgamma agonist.
      ), and was shown to activate transient receptor potential cation channel subfamily V member 1 (TRPV1) channels leading to an influx of Ca2+ ions through TRPV1 (
      • Nieto-Posadas A.
      • Picazo-Juarez G.
      • Llorente I.
      • Jara-Oseguera A.
      • Morales-Lazaro S.
      • Escalante-Alcalde D.
      • Islas L.D.
      • Rosenbaum T.
      Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site.
      ). Studies on gene-targeted mice and human genetic diseases have clearly shown that each receptor has specific roles in both physiological and pathological conditions. For example, LPA has a pivotal role in neurogenesis (
      • Contos J.J.
      • Fukushima N.
      • Weiner J.A.
      • Kaushal D.
      • Chun J.
      Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior.
      ) and has also been implicated in the development of lung fibrosis (
      • Tager A.M.
      • LaCamera P.
      • Shea B.S.
      • Campanella G.S.
      • Selman M.
      • Zhao Z.
      • Polosukhin V.
      • Wain J.
      • Karimi-Shah B.A.
      • Kim N.D.
      • et al.
      The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak.
      ) via LPA1. LPA exhibits unique roles in implantation of fertilized eggs via LPA3 (
      • Ye X.
      • Hama K.
      • Contos J.J.
      • Anliker B.
      • Inoue A.
      • Skinner M.K.
      • Suzuki H.
      • Amano T.
      • Kennedy G.
      • Arai H.
      • et al.
      LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing.
      ) and hair follicle formation via LPA6 (
      • Shimomura Y.
      • Wajid M.
      • Ishii Y.
      • Shapiro L.
      • Petukhova L.
      • Gordon D.
      • Christiano A.M.
      Disruption of P2RY5, an orphan G protein-coupled receptor, underlies autosomal recessive woolly hair.
      ). LPA is produced by at least two pathways where multiple phospholipase activities are involved (
      • Aoki J.
      • Inoue A.
      • Okudaira S.
      Two pathways for lysophosphatidic acid production.
      ). Lysophospholipase D/autotaxin/NPP2 pro­duces LPA from LysoGPs such as LPC, while phosphatidic acid (PA)-selective PLA1α (PA-PLA1α) and PA-PLA1β produce LPA from PA by their PLA1 activities. In contrast, S1P is produced intracellularly by phosphorylation of sphingosine, which is catalyzed by sphingosine kinases (SphK1 and SphK2) (
      • Pyne N.J.
      • Tonelli F.
      • Lim K.G.
      • Long J.S.
      • Edwards J.
      • Pyne S.
      Sphingosine 1-phosphate signalling in cancer.
      ).
      Figure thumbnail gr1
      Fig. 1Structures of lysophospholipids. For glycerophospholipids, the acyl chain can be linked to either the sn-1 or sn-2 position of the glycerol backbone. Each structure containing stearic acid (18:0) at the sn-1 position of glycerol is shown.
      While LPA and S1P have been extensively studied, other LysoGPs have received little attention. LPC is the most abundant LysoGP in humans, with a plasma concentration of several hundred micromoles (
      • Aoki J.
      • Taira A.
      • Takanezawa Y.
      • Kishi Y.
      • Hama K.
      • Kishimoto T.
      • Mizuno K.
      • Saku K.
      • Taguchi R.
      • Arai H.
      Serum lysophosphatidic acid is produced through diverse phospholipase pathways.
      ). A number of in vitro studies have implicated LPC in the activation of macrophages and monocytes (
      • Schmitz G.
      • Ruebsaamen K.
      Metabolism and atherogenic disease association of lysophosphatidylcholine.
      ). However, there is no direct evidence that LPC has a role as a lipid mediator. Previously, several reports indicated that GPCRs, such as G2A, GPR4, and OGR1, reacted with LPC and SPC, a choline-containing lysosphingophospholipid (
      • Xu Y.
      Sphingosylphosphorylcholine and lysophosphatidylcholine: G protein-coupled receptors and receptor-mediated signal transduction.
      ,
      • Kabarowski J.H.
      • Zhu K.
      • Le L.Q.
      • Witte O.N.
      • Xu Y.
      Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A.
      ). However, several of these reports on the receptors for LPC and SPC have been retracted (
      • Witte O.N.
      • Kabarowski J.H.
      • Xu Y.
      • Le L.Q.
      • Zhu K.
      Retraction.
      ), so currently it is not clear if these GPCRs are real receptors for choline-containing LysoGPs (LPC and SPC). Other LysoGPs such as LPG, LPE, LPI, and LysoPS are present at low concentrations in vivo. Although their in vivo roles are unknown, they induce various cellular responses when applied to cells in vitro. Table 1 summarizes the actions of LysoGPs obtained mainly through in vitro experiments, although some results from in vivo tests are also listed for LysoPS and lysophosphatidylthreonine (LPT).
      TABLE 1Action of LysoPS, LPT, LPG, LPE, and LPI
      LysoGPsTarget CellsCellular or Pharmacological ResponsesReceptorReferences
      LysoPSPeritoneal mast cell (rodent)Enhancement of degranulation?(
      • Martin T.W.
      • Lagunoff D.
      Interactions of lysophospholipids and mast cells.
      ,
      • Smith G.A.
      • Hesketh T.R.
      • Plumb R.W.
      • Metcalfe J.C.
      The exogenous lipid requirement for histamine release from rat peritoneal mast cells stimulated by concanavalin A.
      )
      PC12Enhancement of NGF-induced differentiation?(
      • Lourenssen S.
      • Blennerhassett M.G.
      Lysophos­phatidylserine potentiates nerve growth factor-induced differentiation of PC12 cells.
      )
      T lymphocyteGrowth inhibition?(
      • Bellini F.
      • Bruni A.
      Role of a serum phospholipase A1 in the phosphatidylserine-induced T cell inhibition.
      ,
      • Xu Y.
      • Casey G.
      • Mills G.B.
      Effect of lysophospholipids on signaling in the human Jurkat T cell line.
      )
      L2071 (fibroblast)Migration?(
      • Park K.S.
      • Lee H.Y.
      • Kim M.K.
      • Shin E.H.
      • Jo S.H.
      • Kim S.D.
      • Im D.S.
      • Bae Y.S.
      Lysophosphatidylserine stimulates L2071 mouse fibroblast chemotactic migration via a process involving pertussis toxin-sensitive trimeric G-proteins.
      )
      U87 (glioma)Migration?(
      • Lee S.Y.
      • Lee H.Y.
      • Kim S.D.
      • Jo S.H.
      • Shim J.W.
      • Lee H.J.
      • Yun J.
      • Bae Y.S.
      Lysophosphatidylserine stimulates chemotactic migration in U87 human glioma cells.
      )
      MacrophageEngulfmentG2A(
      • Frasch S.C.
      • Berry K.Z.
      • Fernandez-Boyanapalli R.
      • Jin H.S.
      • Leslie C.
      • Henson P.M.
      • Murphy R.C.
      • Bratton D.L.
      NADPH oxidase-dependent generation of lysophosphatidylserine enhances clearance of activated and dying neutrophils via G2A.
      ,
      • Frasch S.C.
      • Fernandez-Boyanapalli R.F.
      • Berry K.Z.
      • Leslie C.C.
      • Bonventre J.V.
      • Murphy R.C.
      • Henson P.M.
      • Bratton D.L.
      Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity.
      )
      Myotube 3T3-L1 (adipocyte)Glucose uptake?(
      • Yea K.
      • Kim J.
      • Lim S.
      • Kwon T.
      • Park H.S.
      • Park K.S.
      • Suh P.G.
      • Ryu S.H.
      Lysophosphatidylserine regulates blood glucose by enhancing glucose transport in myotubes and adipocytes.
      )
      ?Depression, hypothermia (in vivo)?(
      • Iwashita M.
      • Makide K.
      • Nonomura T.
      • Misumi Y.
      • Otani Y.
      • Ishida M.
      • Taguchi R.
      • Tsujimoto M.
      • Aoki J.
      • Arai H.
      • et al.
      Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.
      )
      LPTPeritoneal mast cell (rodent)Enhancement of degranulation?(
      • Iwashita M.
      • Makide K.
      • Nonomura T.
      • Misumi Y.
      • Otani Y.
      • Ishida M.
      • Taguchi R.
      • Tsujimoto M.
      • Aoki J.
      • Arai H.
      • et al.
      Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.
      )
      ?Depression, hypothermia (in vivo)?(
      • Iwashita M.
      • Makide K.
      • Nonomura T.
      • Misumi Y.
      • Otani Y.
      • Ishida M.
      • Taguchi R.
      • Tsujimoto M.
      • Aoki J.
      • Arai H.
      • et al.
      Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.
      )
      LPGOVCAR-3 (ovarian cancer)Intracellular calcium increase?(
      • Park K.S.
      • Kim M.K.
      • Im D.S.
      • Bae Y.S.
      Effect of lysophosphatidylglycerol on several signaling molecules in OVCAR-3 human ovarian cancer cells: involvement of pertussis toxin-sensitive G-protein coupled receptor.
      )
      HUVECERK phospholilation, migration, tube formation?(
      • Lee S.Y.
      • Lee H.Y.
      • Kim S.D.
      • Shim J.W.
      • Bae Y.S.
      Lysophosphatidylglycerol stimulates chemotactic migration and tube formation in human umbilical vein endothelial cells.
      )
      Natural killer cellERK phospholilation, migration?(
      • Jo S.H.
      • Kim S.D.
      • Kim J.M.
      • Lee H.Y.
      • Lee S.Y.
      • Shim J.W.
      • Yun J.
      • Im D.S.
      • Bae Y.S.
      Lysophosphatidylglycerol stimulates chemotactic migration in human natural killer cells.
      )
      Neutrophil, monocyteInhibition of chemokine-induced migration and IL-1β production, intracellular calcium increase?(
      • Shim J.W.
      • Jo S.H.
      • Kim S.D.
      • Lee H.Y.
      • Yun J.
      • Bae Y.S.
      Lysophosphatidylglycerol inhibits formyl peptide receptorlike-1-stimulated chemotactic migration and IL-1beta production from human phagocytes.
      )
      LPEPC12Activation of MAPK, neuronal differentiation?(
      • Nishina A.
      • Kimura H.
      • Sekiguchi A.
      • Fukumoto R.H.
      • Nakajima S.
      • Furukawa S.
      Lysophosphatidylethanolamine in Grifola frondosa as a neurotrophic activator via activation of MAPK.
      )
      SK-OV3 (ovarian cancer)Intracellular calcium increase, migration, invasion?(
      • Park K.S.
      • Lee H.Y.
      • Lee S.Y.
      • Kim M.K.
      • Kim S.D.
      • Kim J.M.
      • Yun J.
      • Im D.S.
      • Bae Y.S.
      Lysophosphatidylethanolamine stimulates chemotactic migration and cellular invasion in SK-OV3 human ovarian cancer cells: involvement of pertussis toxin-sensitive G-protein coupled receptor.
      )
      MDA-MB-231 (breast cancer)Intracellular calcium increaseLPA1CD97(
      • Park S.J.
      • Lee K.P.
      • Kang S.
      • Chung H.Y.
      • Bae Y.S.
      • Okajima F.
      • Im D.S.
      Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in MDA-MB-231 breast cancer cells.
      )
      LPIPancreatic isletInsulin release?(
      • Metz S.A.
      Lysophosphatidylinositol, but not lysophosphatidic acid, stimulates insulin release. A possible role for phospholipase A2 but not de novo synthesis of lysophospholipid in pancreatic islet function.
      )
      Hippocampal neuronPrevention of ischemia-induced cell death (in vivo)?(
      • Blondeau N.
      • Lauritzen I.
      • Widmann C.
      • Lazdunski M.
      • Heurteaux C.
      A potent protective role of lysophospholipids against global cerebral ischemia and glutamate excitotoxicity in neuronal cultures.
      )
      Ras-transformed thyroid epithelial cellProliferation?(
      • Falasca M.
      • Corda D.
      Elevated levels and mitogenic activity of lysophosphatidylinositol in k-ras-transformed epithelial cells.
      )
      PC12Intracellular calcium increase, exocytosis?(
      • Ma M.T.
      • Yeo J.F.
      • Farooqui A.A.
      • Zhang J.
      • Chen P.
      • Ong W.Y.
      Differential effects of lysophospholipids on exocytosis in rat PC12 cells.
      )
      Endothelial cellWound healing?(
      • Murugesan G.
      • Fox P.L.
      Role of lysophosphatidylcholine in the inhibition of endothelial cell motility by oxidized low density lipoprotein.
      )
      One of the reasons that these minor LysoGPs have not been carefully examined is that their receptors and synthetic enzymes have not been identified. However, GPCRs that react specifically with either LysoPS or LPI, have recently been reported. In this review we will summarize the receptors, especially GPCRs, for LysoPS and LPI, and their possible functions through their receptors.

      Lysops

      Actions of LysoPS

      LysoPS is known to induce several cellular responses both in vitro and in vivo (Fig. 2). The most characterized response has been the stimulatory response of mast cell degranulation (
      • Martin T.W.
      • Lagunoff D.
      Interactions of lysophospholipids and mast cells.
      ,
      • Smith G.A.
      • Hesketh T.R.
      • Plumb R.W.
      • Metcalfe J.C.
      The exogenous lipid requirement for histamine release from rat peritoneal mast cells stimulated by concanavalin A.
      ). In vitro, LysoPS enhances histamine release from peritoneal rodent mast cells triggered by the cross-linking of high-affinity IgE receptors (FcεRI). It also induces rapid degranulation of mast cells and consequent anaphylactic shock and hypothermia when administered intravenously in rodents (
      • Bruni A.
      • Bigon E.
      • Battistella A.
      • Boarato E.
      • Mietto L.
      • Toffano G.
      Lysophosphatidylserine as histamine releaser in mice and rats.
      ,
      • Iwashita M.
      • Makide K.
      • Nonomura T.
      • Misumi Y.
      • Otani Y.
      • Ishida M.
      • Taguchi R.
      • Tsujimoto M.
      • Aoki J.
      • Arai H.
      • et al.
      Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.
      ). The mast cell degranulation-stimulating activity is not induced by other LysoGPs including LPA, LPC, LPE, LPG, and LPI, and strictly requires the serine residue of LysoPS. It also strictly re­quires the overall structure of the serine residue of LysoPS, because modification of the serine residue completely abolishes the mast cell degranulation-stimulating activity. LysoPS directly acts on mast cells, because a deoxy analog of LysoPS (2-deoxy-LysoPS), which lacks the sn-2 hydroxyl group and is resistant to the reacylation reaction to PS, has activity similar to that of LysoPS.
      Figure thumbnail gr2
      Fig. 2Biological roles of LysoPS. LysoPS induces several cellular responses both in vitro and in vivo. LysoPS enhances antigen-triggered degranulation of mast cells and NGF-induced neurite outgrowth, suppresses T cell proliferation, stimulates migration of fibroblasts, and enhances apoptotic cell-engulfment by macrophages.
      LysoPS also enhances Nerve Growth Factor (NGF)-induced neurite outgrowth in PC12 cells (
      • Lourenssen S.
      • Blennerhassett M.G.
      Lysophos­phatidylserine potentiates nerve growth factor-induced differentiation of PC12 cells.
      ), suppresses proliferation of isolated human T lymphocytes (
      • Bellini F.
      • Bruni A.
      Role of a serum phospholipase A1 in the phosphatidylserine-induced T cell inhibition.
      ), stimulates migration of fibroblasts (
      • Lee S.Y.
      • Lee H.Y.
      • Kim S.D.
      • Jo S.H.
      • Shim J.W.
      • Lee H.J.
      • Yun J.
      • Bae Y.S.
      Lysophosphatidylserine stimulates chemotactic migration in U87 human glioma cells.
      ,
      • Park K.S.
      • Lee H.Y.
      • Kim M.K.
      • Shin E.H.
      • Jo S.H.
      • Kim S.D.
      • Im D.S.
      • Bae Y.S.
      Lysophosphatidylserine stimulates L2071 mouse fibroblast chemotactic migration via a process involving pertussis toxin-sensitive trimeric G-proteins.
      ), regulates cytochrome P450 activity (
      • Cho E.Y.
      • Yun C.H.
      • Chae H.Z.
      • Chae H.J.
      • Ahn T.
      Lysophosphatidylserine-induced functional switch of human cytochrome P450 1A2 and 2E1 from monooxygenase to phospholipase D.
      ), and enhances apoptotic cell-engulfment by macrophages (
      • Frasch S.C.
      • Zemski-Berry K.
      • Murphy R.C.
      • Borregaard N.
      • Henson P.M.
      • Bratton D.L.
      Lysophospholipids of different classes mobilize neutrophil secretory vesicles and induce redundant signaling through G2A.
      ) (Fig. 2). In the host-parasite interaction of schistosomes, LysoPS was identified as a Toll-like receptor 2 (TLR2)-activating molecule that prolonged the survival of the parasite and limited its pathology to the host (
      • van der Kleij D.
      • Latz E.
      • Brouwers J.F.
      • Kruize Y.C.
      • Schmitz M.
      • Kurt-Jones E.A.
      • Espevik T.
      • de Jong E.C.
      • Kapsenberg M.L.
      • Golenbock D.T.
      • et al.
      A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization.
      ).
      Recently, Bratton and colleagues showed that LysoPS was generated in neutrophils by an oxidation-dependent mechanism and served as an endogenous anti-inflammatory mediator by stimulating the clearance of recruited neutrophils by macrophages, contributing to the resolution of inflammation (
      • Frasch S.C.
      • Fernandez-Boyanapalli R.F.
      • Berry K.A.
      • Murphy R.C.
      • Leslie C.C.
      • Nick J.A.
      • Henson P.M.
      • Bratton D.L.
      Neutrophils regulate tissue Neutrophilia in inflammation via the oxidant-modified lipid lysophosphatidylserine.
      ,
      • Frasch S.C.
      • Berry K.Z.
      • Fernandez-Boyanapalli R.
      • Jin H.S.
      • Leslie C.
      • Henson P.M.
      • Murphy R.C.
      • Bratton D.L.
      NADPH oxidase-dependent generation of lysophosphatidylserine enhances clearance of activated and dying neutrophils via G2A.
      ,
      • Frasch S.C.
      • Fernandez-Boyanapalli R.F.
      • Berry K.Z.
      • Leslie C.C.
      • Bonventre J.V.
      • Murphy R.C.
      • Henson P.M.
      • Bratton D.L.
      Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity.
      ). In addition, their results suggest that a GPCR (G2A) on macrophages is responsible for the clearance of neutrophils by macrophages, raising the possibility that LysoPS is an endogenous ligand for G2A. G2A was once proposed as a receptor for LPC, but the proposal was later retracted (
      • Kabarowski J.H.
      • Zhu K.
      • Le L.Q.
      • Witte O.N.
      • Xu Y.
      Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A.
      ). Now many reports have confirmed that G2A is a receptor for protons and for 9-HODE, a kind of oxidized fatty acid (linoleic acid) (
      • Murakami N.
      • Yokomizo T.
      • Okuno T.
      • Shimizu T.
      G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine.
      ,
      • Obinata H.
      • Hattori T.
      • Nakane S.
      • Tatei K.
      • Izumi T.
      Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A.
      ). It is not clear if G2A directly recognizes LysoPS.
      Because LysoPS induces various cellular responses in a LysoPS-specific manner, its actions may be mediated by LysoPS receptors. Recently, several orphan GPCRs were identified as LysoPS receptors. These include GPR34, P2Y10, A630033H20, and GPR174, all of which are P2Y family members (
      • Sugo T.
      • Tachimoto H.
      • Chikatsu T.
      • Murakami Y.
      • Kikukawa Y.
      • Sato S.
      • Kikuchi K.
      • Nagi T.
      • Harada M.
      • Ogi K.
      • et al.
      Identification of a lysophosphatidylserine receptor on mast cells.
      ,
      • Inoue A.
      • Ishiguro J.
      • Kitamura H.
      • Arima N.
      • Okutani M.
      • Shuto A.
      • Higashiyama S.
      • Ohwada T.
      • Arai H.
      • Makide K.
      • et al.
      TGFα shedding assay: an accurate and versatile method for detecting GPCR activation.
      ) (Fig. 3). Although new nomenclature for these LysoPS receptors was recently proposed by Kihara et al. (

      KiharaY.MaceykaM.SpiegelS.ChunJ.. Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br. J. Pharmacol., 171: 3575–3594.

      ), we propose that GPR34, P2Y10, A630033H20, and GPR174 be designated as LPS1, LPS2, LPS2-like (LPS2L), and LPS3, respectively, according to the nomenclature of lysophospholipid receptors and the original report (
      • Inoue A.
      • Ishiguro J.
      • Kitamura H.
      • Arima N.
      • Okutani M.
      • Shuto A.
      • Higashiyama S.
      • Ohwada T.
      • Arai H.
      • Makide K.
      • et al.
      TGFα shedding assay: an accurate and versatile method for detecting GPCR activation.
      ).
      Figure thumbnail gr3
      Fig. 3Phylogenetic tree of the amino acid sequences of human P2Y family members.

      GPR34/LPS1

      GPR34 was first isolated from a human fetal brain cDNA library based on its sequence homology with the platelet-activating factor (PAF) receptor (
      • Marchese A.
      • Sawzdargo M.
      • Nguyen T.
      • Cheng R.
      • Heng H.H.
      • Nowak T.
      • Im D.S.
      • Lynch K.R.
      • George S.R.
      • O'Dowd B.F.
      Discovery of three novel orphan G-protein-coupled receptors.
      ,
      • Schöneberg T.
      • Schulz A.
      • Grosse R.
      • Schade R.
      • Henklein P.
      • Schultz G.
      • Gudermann T.
      A novel subgroup of class I G-protein-coupled receptors.
      ). GPR34 is preserved among vertebrates and GPR34 sequences are found in fish including shark, fugu, zebra­fish, and carp, suggesting that GPR34 has existed for at least 450 million years (
      • Schulz A.
      • Schoneberg T.
      The structural evolution of a P2Y-like G-protein-coupled receptor.
      ). GPR34 is thought to be a member of P2Y family (Fig. 3), because GPR34 has some amino acid residues that are characteristic of P2Y family members. The P2Y family includes receptors for nucleotide (P2Y1, P2Y2, P2Y12, and P2Y13), UDP-glucose (P2Y14), LPAs (P2Y9/LPA4, GPR92/LPA5, and P2Y5/LPA6), and the orphan GPCRs (GPR87, GPR171, and GPR82). Interestingly, GPR34 does not contain a charged basic residue within Transmembrane helix 7 (TM7) that other P2Y family members have and that is essential for the binding of nucleotide ligands such as ATP (
      • Jiang Q.
      • Guo D.
      • Lee B.X.
      • Van Rhee A.M.
      • Kim Y.C.
      • Nicholas R.A.
      • Schachter J.B.
      • Harden T.K.
      • Jacobson K.A.
      A mutational analysis of residues essential for ligand recognition at the human P2Y1 receptor.
      ).
      In 2006, in the course of a ligand fishing study for GPR34, Sugo et al. (
      • Sugo T.
      • Tachimoto H.
      • Chikatsu T.
      • Murakami Y.
      • Kikukawa Y.
      • Sato S.
      • Kikuchi K.
      • Nagi T.
      • Harada M.
      • Ogi K.
      • et al.
      Identification of a lysophosphatidylserine receptor on mast cells.
      ) found that LysoPS is a ligand for GPR34. They showed that LysoPS caused a dose-dependent inhibition of forskolin-stimulated cAMP accumulation in human GPR34-expressing Chinese hamster ovary (CHO) cells. They also showed that LysoPS induced phosphorylation of ERK in GPR34-expressing CHO cells. The response was completely abolished by treatment with pertussis toxin, indicating that GPR34 couples to a Gi/o-type G-protein. GPR34 did not respond to other lysophospholipids, including LPA, S1P, LPC, and LPE. Notably, lysophosphatidyl D-serine (D-LysoPS) as well as LPT were later shown to be poor agonists (
      • Iwashita M.
      • Makide K.
      • Nonomura T.
      • Misumi Y.
      • Otani Y.
      • Ishida M.
      • Taguchi R.
      • Tsujimoto M.
      • Aoki J.
      • Arai H.
      • et al.
      Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.
      ), indicating that GPR34 specifically and strictly recognizes the L-LysoPS moiety of LysoPS.
      There is some controversy over whether LysoPS is a real ligand for mammalian GPR34 (
      • Liebscher I.
      • Muller U.
      • Teupser D.
      • Engemaier E.
      • Engel K.M.
      • Ritscher L.
      • Thor D.
      • Sangkuhl K.
      • Ricken A.
      • Wurm A.
      • et al.
      Altered immune response in mice deficient for the G protein-coupled receptor GPR34.
      ). On the one hand, Liebscher et al. (
      • Liebscher I.
      • Muller U.
      • Teupser D.
      • Engemaier E.
      • Engel K.M.
      • Ritscher L.
      • Thor D.
      • Sangkuhl K.
      • Ricken A.
      • Wurm A.
      • et al.
      Altered immune response in mice deficient for the G protein-coupled receptor GPR34.
      ) demonstrated that GPR34 from carp, a kind of fish, did react strongly with LysoPS. On the other hand, the result of the initial study by Sugo et al. (
      • Sugo T.
      • Tachimoto H.
      • Chikatsu T.
      • Murakami Y.
      • Kikukawa Y.
      • Sato S.
      • Kikuchi K.
      • Nagi T.
      • Harada M.
      • Ogi K.
      • et al.
      Identification of a lysophosphatidylserine receptor on mast cells.
      ) was confirmed by Kitamura et al. (
      • Kitamura H.
      • Makide K.
      • Shuto A.
      • Ikubo M.
      • Inoue A.
      • Suzuki K.
      • Sato Y.
      • Nakamura S.
      • Otani Y.
      • Ohwada T.
      • et al.
      GPR34 is a receptor for lysophosphatidylserine with a fatty acid at the sn-2 position.
      ), in which activation of GPR34 was evaluated by a Ca2+ mobilization assay and by a newly developed transforming growth factor (TGF)α shedding assay. In both assays, mammalian GPR34s from human, rat, and mouse origins reacted specifically with LysoPS, but not with other LysoGPs Notably, GPR34 reacted most strongly with LysoPS species with an unsaturated fatty acid at the sn-2 position. A similar ligand preference was observed using chemically synthesized LysoPS analogs. To confirm this result, GPR34 was activated by treating the cells with phosphatidylserine-specific PLA1 (PS-PLA1), which is capable of producing 2-acyl-LysoPS from PS on the cell surface. We also cloned two orthologs of GPR34 from zebrafish (zGPR34a and zGPR34b) and examined their reactivities with LysoPS. In the TGFα shedding assay, the two orthologs reacted much more strongly with LysoPS than did mammalian GPR34 (Fig. 4). All the experimental data strongly suggested that LysoPS, especially LysoPS with an unsaturated fatty acid at the sn-2 position, is the endogenous ligand for both mammalian and fish GPR34s.
      Figure thumbnail gr4
      Fig. 4Reaction of two GPR34 orthologs in zebrafish to LysoPS. A: Reactivity of human, mouse, and zebrafish GPR34 to LysoPS (1-oleoyl-LysoPS) by TGFα shedding assay, in which activation of GPCR was monitored by ectodomain shedding of alkaline phosphatase (AP)-tagged TGFα downstream of G protein signaling. Note that zebrafish have two GPR34 orthologs (zGPR34a and zGPR34b). B: Comparison of GPR34 amino acid sequences from different species.
      GPR34 mRNA is expressed in many tissues, but is most highly expressed in mast cells (
      • Sugo T.
      • Tachimoto H.
      • Chikatsu T.
      • Murakami Y.
      • Kikukawa Y.
      • Sato S.
      • Kikuchi K.
      • Nagi T.
      • Harada M.
      • Ogi K.
      • et al.
      Identification of a lysophosphatidylserine receptor on mast cells.
      ). Thus, it was once proposed that LysoPS enhanced mast cell degranulation through GPR34. However, as stated above, LPT, a potent inducer of mast cell degranulation, did not activate GPR34 (
      • Iwashita M.
      • Makide K.
      • Nonomura T.
      • Misumi Y.
      • Otani Y.
      • Ishida M.
      • Taguchi R.
      • Tsujimoto M.
      • Aoki J.
      • Arai H.
      • et al.
      Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.
      ). In addition, peritoneal mast cells from GPR34-deficient mice still responded to LysoPS (
      • Liebscher I.
      • Muller U.
      • Teupser D.
      • Engemaier E.
      • Engel K.M.
      • Ritscher L.
      • Thor D.
      • Sangkuhl K.
      • Ricken A.
      • Wurm A.
      • et al.
      Altered immune response in mice deficient for the G protein-coupled receptor GPR34.
      ). Thus, it is likely that GPR34 is not involved in the mast cell degranulation response induced by LysoPS. Cuprizone, a demyelinating toxin, was found to upregulate the expression of GPR34 in activated microglia, which suggests that GPR34, and thus LysoPS, have roles in neuroinflammation (
      • Bédard A.
      • Tremblay P.
      • Chernomoretz A.
      • Vallières L.
      Identification of genes preferentially expressed by microglia and upregulated during cuprizone-induced inflammation.
      ). In addition, recent gene array analysis revealed that GPR34 is highly expressed in microglia in both humans and mice (
      • Butovsky O.
      • Jedrychowski M.P.
      • Moore C.S.
      • Cialic R.
      • Lanser A.J.
      • Gabriely G.
      • Koeglsperger T.
      • Dake B.
      • Wu P.M.
      • Doykan C.E.
      • et al.
      Identification of a unique TGF-beta-dependent molecular and functional signature in microglia.
      ). Interestingly, other P2Y receptors, such as P2Y6, -12, and -13, are expressed in microglial cells and are involved in the chemotaxis of microglia (P2Y12 and -13) (
      • Nasu-Tada K.
      • Koizumi S.
      • Inoue K.
      Involvement of beta1 integrin in microglial chemotaxis and proliferation on fibronectin: different regulations by ADP through PKA.
      ) and microglial phagocytosis (P2Y6) (
      • Koizumi S.
      • Shigemoto-Mogami Y.
      • Nasu-Tada K.
      • Shinozaki Y.
      • Ohsawa K.
      • Tsuda M.
      • Joshi B.V.
      • Jacobson K.A.
      • Kohsaka S.
      • Inoue K.
      UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis.
      ). GPR34 may have similar roles in microglial cells.
      The in vivo role of LysoPS through GPR34 is not clear. GPR34 KO mice appeared healthy and normal but when GPR34 KO and WT mice were immunologically challenged with methylated BSA or bacterial infection, the KO mice showed fewer inflammatory cells and greater cytokine production than the WT mice (
      • Liebscher I.
      • Muller U.
      • Teupser D.
      • Engemaier E.
      • Engel K.M.
      • Ritscher L.
      • Thor D.
      • Sangkuhl K.
      • Ricken A.
      • Wurm A.
      • et al.
      Altered immune response in mice deficient for the G protein-coupled receptor GPR34.
      ) (Table 2). Because GPR34 is highly expressed in mononuclear cells of the immune system, LysoPS appears to serve as an immunomodulator through GPR34 in response to immunological challenges. Further studies are needed to elucidate the biological significance of LysoPS signaling via GPR34. Interestingly, ectopic expression of GPR34 was reported in clinical samples such as lymphoma and stomach cancer, indicating that aberrant GPR34 signaling is a cause or effect of tumor growth (
      • Yu W.
      • Ma S.
      • Wang L.
      • Zuo B.
      • Li M.
      • Qiao Z.
      • Pan X.
      • Liu Y.
      • Wang J.
      Upregulation of GPR34 expression affects the progression and prognosis of human gastric adenocarcinoma by PI3K/PDK1/AKT pathway.
      ,
      • Ansell S.M.
      • Akasaka T.
      • McPhail E.
      • Manske M.
      • Braggio E.
      • Price-Troska T.
      • Ziesmer S.
      • Secreto F.
      • Fonseca R.
      • Gupta M.
      • et al.
      t(X;14)(p11;q32) in MALT lymphoma involving GPR34 reveals a role for GPR34 in tumor cell growth.
      ).
      TABLE 2Receptors for LysoPS and LPI
      LysoGPsReceptorExpressionPossible FunctionsReferences
      LysoPSGPR34/LPS1UbiquitousSuppression of cytokine production upon infection(
      • Liebscher I.
      • Muller U.
      • Teupser D.
      • Engemaier E.
      • Engel K.M.
      • Ritscher L.
      • Thor D.
      • Sangkuhl K.
      • Ricken A.
      • Wurm A.
      • et al.
      Altered immune response in mice deficient for the G protein-coupled receptor GPR34.
      )
      P2Y10/LPS2Lymphoid organs?(
      • Rao S.
      • Garrett-Sinha L.A.
      • Yoon J.
      • Simon M.C.
      The Ets factors PU.1 and Spi-B regulate the transcription in vivo of P2Y10, a lymphoid restricted heptahelical receptor.
      )
      A630033H20/LPS2LLymphoid organs?
      GPR174/LPS3Lymphoid organsAutoimmune diseases (Basedow's disease)(
      • Chu X.
      • Shen M.
      • Xie F.
      • Miao X.J.
      • Shou W.H.
      • Liu L.
      • Yang P.P.
      • Bai Y.N.
      • Zhang K.Y.
      • Yang L.
      • et al.
      An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves' disease.
      )
      LPIGPR55UbiquitousBone morphogenesis, angiogenesis, cancer cell regulation, inflammation, pain, obesity(
      • Balenga N.A.
      • Aflaki E.
      • Kargl J.
      • Platzer W.
      • Schroder R.
      • Blattermann S.
      • Kostenis E.
      • Brown A.J.
      • Heinemann A.
      • Waldhoer M.
      GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils.
      • Staton P.C.
      • Hatcher J.P.
      • Walker D.J.
      • Morrison A.D.
      • Shapland E.M.
      • Hughes J.P.
      • Chong E.
      • Mander P.K.
      • Green P.J.
      • Billinton A.
      • et al.
      The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain.
      ,
      • Ross R.A.
      L-α-lysophosphatidylinositol meets GPR55: a deadly relationship.
      ,
      • Moreno-Navarrete J.M.
      • Catalan V.
      • Whyte L.
      • Diaz-Arteaga A.
      • Vazquez-Martinez R.
      • Rotellar F.
      • Guzman R.
      • Gomez-Ambrosi J.
      • Pulido M.R.
      • Russell W.R.
      • et al.
      The L-α-lysophosphatidylinositol/GPR55 system and its potential role in human obesity.
      )

      P2Y10/LPS2

      Using our TGFα shedding assay (
      • Inoue A.
      • Ishiguro J.
      • Kitamura H.
      • Arima N.
      • Okutani M.
      • Shuto A.
      • Higashiyama S.
      • Ohwada T.
      • Arai H.
      • Makide K.
      • et al.
      TGFα shedding assay: an accurate and versatile method for detecting GPCR activation.
      ), we found that LysoPS specifically reacted with 3 of 60 orphan GPCRs tested (P2Y10, A630033H20, and GPR174), all of which are P2Ys (Fig. 3). In the TGFα shedding assay, P2Y10-expressing cells reacted with LysoPS, but not with other LysoGPs Importantly, P2Y10 was not activated by D-LysoPS or LPT, demonstrating that P2Y10 strictly recognized the serine residue of LysoPS. The biological role of P2Y10 is not known at present. Expression of P2Y10 is restricted to lymphoid organs such as spleen, thymus, and lymph nodes. The expression of P2Y10 is dependent on PU.1 and Spi-B, two highly related Ets transcription factors (
      • Rao S.
      • Garrett-Sinha L.A.
      • Yoon J.
      • Simon M.C.
      The Ets factors PU.1 and Spi-B regulate the transcription in vivo of P2Y10, a lymphoid restricted heptahelical receptor.
      ). Ets transcription factors are involved in a variety of mammalian developmental processes at the cellular, tissue, and organ levels (
      • Maroulakou I.G.
      • Bowe D.B.
      Expression and function of Ets transcription factors in mammalian development: a regulatory network.
      ). In PU.1+/−Spi-B−/− mice, the expression of P2Y10 is dramatically reduced. These Ets transcription factors have a role in the signal transduction of B cell receptors (
      • Garrett-Sinha L.A.
      • Su G.H.
      • Rao S.
      • Kabak S.
      • Hao Z.
      • Clark M.R.
      • Simon M.C.
      PU.1 and Spi-B are required for normal B cell receptor-mediated signal transduction.
      ), which suggests that P2Y10 has a role in regulating BCR signaling. A comprehensive expression analysis in the database (http://biogps.org/) indicated that P2Y10 is expressed in both B and T cells.
      P2Y10 couples with Gα12/13 but not with other G proteins. Gα12/13 signaling in T cells has a role to downregulate the cellular function of T cells. Genetic inactivation of both Gα12 and Gα13 genes enhanced the proliferation and adhesive properties of T cells (
      • Herroeder S.
      • Reichardt P.
      • Sassmann A.
      • Zimmermann B.
      • Jaeneke D.
      • Hoeckner J.
      • Hollmann M.W.
      • Fischer K.D.
      • Vogt S.
      • Grosse R.
      • et al.
      Guanine nucleotide-binding proteins of the G12 family shape immune functions by controlling CD4+ T cell adhesiveness and motility.
      ). Interestingly, LysoPS suppressed the proliferation of activated T cells in vitro (
      • Bellini F.
      • Bruni A.
      Role of a serum phospholipase A1 in the phosphatidylserine-induced T cell inhibition.
      ), which raises the possibility that LysoPS has its role in T cells through P2Y10.
      It was reported that in CHO cells expressing human P2Y10, both LPA and S1P evoked a Ca2+ response (
      • Murakami M.
      • Shiraishi A.
      • Tabata K.
      • Fujita N.
      Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1-phosphate and lysophosphatidic acid receptor.
      ). This suggested that P2Y10 is a receptor for both LPA and S1P. However, attempts to repeat the experiment were unsuccessful (
      • Inoue A.
      • Ishiguro J.
      • Kitamura H.
      • Arima N.
      • Okutani M.
      • Shuto A.
      • Higashiyama S.
      • Ohwada T.
      • Arai H.
      • Makide K.
      • et al.
      TGFα shedding assay: an accurate and versatile method for detecting GPCR activation.
      ). As stated, P2Y10 was not activated by LysoPS analogs such as D-LysoPS and LPT. In addition, two other GPCRs that are close homologs of P2Y10 (GPR174 and A630033H20) are also activated specifically by LysoPS. Thus, it can safely be said that P2Y10 recognizes strictly the structure of the serine moiety of LysoPS. We thus propose to name the new LysoPS receptor P2Y10/LPS2.

      A630033H20/LPS2L

      A630033H20 was also shown to react specifically with LysoPS (
      • Inoue A.
      • Ishiguro J.
      • Kitamura H.
      • Arima N.
      • Okutani M.
      • Shuto A.
      • Higashiyama S.
      • Ohwada T.
      • Arai H.
      • Makide K.
      • et al.
      TGFα shedding assay: an accurate and versatile method for detecting GPCR activation.
      ). A630033H20 is the closest homolog of P2Y10, with a 75% homology to P2Y10 at the amino acid level. The A630033H20 locus is next to that of P2Y10, indicating that these two genes were generated by gene duplication. Interestingly, the human A630033H20 gene identified in the database, has frame shift mutations that result in a shortened form composed of 114 amino acids. The product of the human gene does not function as a LysoPS receptor (A. Inoue, unpublished observations), indicating that the gene is a pseudogene. In rodents, however, A630033H20 is functional; and according to the public database, it is highly expressed in lymphoid organs such as spleen and lymph nodes. In mice, the expression patterns of A630033H20 and P2Y10 are similar, so that these receptors may have redundant roles. Like P2Y10, A630033H20 coupled with Gα12/13 (
      • Inoue A.
      • Ishiguro J.
      • Kitamura H.
      • Arima N.
      • Okutani M.
      • Shuto A.
      • Higashiyama S.
      • Ohwada T.
      • Arai H.
      • Makide K.
      • et al.
      TGFα shedding assay: an accurate and versatile method for detecting GPCR activation.
      ). Because of these properties, we propose to name A630033H20 as LPS2L (LPS2-like).

      GPR174/LPS3

      GPR174 shows the highest homology to P2Y10 and A630033H20 with ∼50% identity at the amino acid level. These three GPCRs seem to form a subfamily within the P2Y family (Fig. 3). Like P2Y10 and A630033H20, GPR174 is activated by LysoPS (
      • Sugita K.
      • Yamamura C.
      • Tabata K.
      • Fujita N.
      Expression of orphan G-protein coupled receptor GPR174 in CHO cells induced morphological changes and proliferation delay via increasing intracellular cAMP.
      ). The expression pattern of GPR174 is similar to the expression pattern of P2Y10 and A630033H20 with high expression in lymphoid tissues. However, GPR174 is also strongly expressed in some melanoma cells (
      • Qin Y.
      • Verdegaal E.M.
      • Siderius M.
      • Bebelman J.P.
      • Smit M.J.
      • Leurs R.
      • Willemze R.
      • Tensen C.P.
      • Osanto S.
      Quantitative expression profiling of G-protein-coupled receptors (GPCRs) in metastatic melanoma: the constitutively active orphan GPCR GPR18 as novel drug target.
      ). GPR174 mainly coupled with both Gαs and Gα13 (
      • Sugita K.
      • Yamamura C.
      • Tabata K.
      • Fujita N.
      Expression of orphan G-protein coupled receptor GPR174 in CHO cells induced morphological changes and proliferation delay via increasing intracellular cAMP.
      ). Given that Gα13 signaling is induced by the three LysoPS receptors (P2Y10, A630033H20, and GPR174) which show similar expression patterns, it is likely that these three LysoPS receptors share redundant functions in activating the Gα13 pathway. On the other hand, because there is only one LysoPS receptor (GPR174) that is coupled with Gαs, GPR174 may have a unique role in regulating Gαs signaling. Like P2Y10 and A630033H20, GPR174 is on Xq21.1 in humans; and, interestingly, its locus is close to loci associated with the risk for Graves' disease, an autoimmune disease (
      • Chu X.
      • Shen M.
      • Xie F.
      • Miao X.J.
      • Shou W.H.
      • Liu L.
      • Yang P.P.
      • Bai Y.N.
      • Zhang K.Y.
      • Yang L.
      • et al.
      An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves' disease.
      ,
      • Szymański K.
      • Miśkiewicz P.
      • Pirko K.
      • Jurecka-Lubieniecka B.
      • Kula D.
      • Hasse-Lazar K.
      • Krajewski P.
      • Bednarczuk T.
      • Ploski R.
      rs3827440, a nonsynonymous single nucleotide polymorphism within GPR174 gene in X chromosome, is associated with Graves' disease in Polish Caucasian population.
      ) (Table 2). Thus, LysoPS may serve as an immunomodulator through GPR174.

      LPI

      Actions of LPI

      The role of LPI was first demonstrated in 1986, when it was shown to stimulate the release of insulin from pancreatic cells (
      • Metz S.A.
      Lysophosphatidylinositol, but not lysophosphatidic acid, stimulates insulin release. A possible role for phospholipase A2 but not de novo synthesis of lysophospholipid in pancreatic islet function.
      ). Subsequent studies found that LPI is produced in various cell systems and that it induces a number of cellular events (
      • Piñeiro R.
      • Falasca M.
      Lysophosphatidylinositol signalling: new wine from an old bottle.
      ). In addition, LPI is a biomarker for certain cancers (
      • Blondeau N.
      • Lauritzen I.
      • Widmann C.
      • Lazdunski M.
      • Heurteaux C.
      A potent protective role of lysophospholipids against global cerebral ischemia and glutamate excitotoxicity in neuronal cultures.
      ) and gynecological diseases. LPI also has neuroprotective effects in a model of global cerebral ischemia and in a model of glutamate excitotoxicity in neuronal cultures (
      • Blondeau N.
      • Lauritzen I.
      • Widmann C.
      • Lazdunski M.
      • Heurteaux C.
      A potent protective role of lysophospholipids against global cerebral ischemia and glutamate excitotoxicity in neuronal cultures.
      ). LPI was also identified as a ligand for GPR55 (
      • Oka S.
      • Nakajima K.
      • Yamashita A.
      • Kishimoto S.
      • Sugiura T.
      Identification of GPR55 as a lysophosphatidylinositol receptor.
      ), which has roles in cancer progression, bone regulation, endothelial function, inflammation, and pain (Fig. 5, Table 1).
      Figure thumbnail gr5
      Fig. 5Biological roles of LPI/GPR55. GPR55 KO mice show phenotypes in bone mass, inflammation, angiogenesis, and hyperalgesia.

      GPR55

      Human GPR55 is 319 amino acids long and its gene maps to human chromosome 2q37. A database search for sequences similar to human GPR55 revealed that GPR55 is conserved among vertebrates from fish to mammals. The closest homologs to GPR55, as judged by amino acid homology, are LPA6/P2Y5 (29%), LPA4/GPR23 (30%), GPR35 (27%), and the chemokine receptor CCR4 (23%).
      Two cannabinoid receptors (CB1 and CB2) have been identified. GPR55 has been proposed to be another cannabinoid receptor even though it has no similarity to CB1 and CB2. Classically, most cannabinoid ligands interact with CB1 and CB2. However, pharmacological data and studies using CB1 and CB2 KO mice have suggested that additional cannabinoid-sensitive targets exist. As a result, AstraZeneca and GlaxoSmithKline suggested that GPR55 was activated by a range of endogenous plant and synthetic cannabinoids (
      • Ryberg E.
      • Larsson N.
      • Sjogren S.
      • Hjorth S.
      • Hermansson N.O.
      • Leonova J.
      • Elebring T.
      • Nilsson K.
      • Drmota T.
      • Greasley P.J.
      The orphan receptor GPR55 is a novel cannabinoid receptor.
      ,
      • Johns D.G.
      • Behm D.J.
      • Walker D.J.
      • Ao Z.
      • Shapland E.M.
      • Daniels D.A.
      • Riddick M.
      • Dowell S.
      • Staton P.C.
      • Green P.
      • et al.
      The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects.
      ). However, to date, the most potent ligand identified for GPR55 is LPI (
      • Yamashita A.
      • Oka S.
      • Tanikawa T.
      • Hayashi Y.
      • Nemoto-Sasaki Y.
      • Sugiura T.
      The actions and metabolism of lysophosphatidylinositol, an endogenous agonist for GPR55.
      ). Although GPR55 clearly interacts with certain cannabinoid ligands, it is currently not clear whether CB1/CB2-independent cannabinoid actions are mediated by GPR55.
      GPR55 appears primarily to couple to a Gα13. In HEK293 cells, as well as in human neutrophils, activation of GPR55 by LPI led to the formation of filamentous actin, which was dependent on the presence of functional Gα13, RhoA, and ROCK (
      • Henstridge C.M.
      • Balenga N.A.
      • Ford L.A.
      • Ross R.A.
      • Waldhoer M.
      • Irving A.J.
      The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation.
      ,
      • Balenga N.A.
      • Aflaki E.
      • Kargl J.
      • Platzer W.
      • Schroder R.
      • Blattermann S.
      • Kostenis E.
      • Brown A.J.
      • Heinemann A.
      • Waldhoer M.
      GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils.
      ). In a single-cell Ca2+ imaging approach, activation of GPR55 also led to an oscillatory Ca2+ response. In this response, phospholipase C-mediated inositol 1,4,5-triphosphate formation and subsequent release of Ca2+ from internal stores occur in a downstream signaling cascade involving Gα13-RhoA-ROCK. Thus, GPR55 signaling evoked by LPI activates RhoA and ROCK and induces cytoskeletal change and prolonged and oscillatory Ca2+ release from intracellular stores, culminating in the induction of a variety of transcription factors with the potential to significantly alter cellular physiology.
      At the cellular level, LPI induced many cellular responses through GPR55 (Tables 1, 2), which implicates the LPI-GPR55 axis in many pathophysiological processes. Male GPR55 KO mice exhibit a clear phenotype with high bone mass, although this is not observed in females (
      • Whyte L.S.
      • Ryberg E.
      • Sims N.A.
      • Ridge S.A.
      • Mackie K.
      • Greasley P.J.
      • Ross R.A.
      • Rogers M.J.
      The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo.
      ). GPR55 is expressed in osteoclasts, and GPR55 activation in the cells results in osteoclastogenesis, cell polarization and bone resorption. In male GPR55 KO mice, osteoclast numbers were increased significantly. These findings indicate that the LPI-GPR55 axis affects differentiation and/or proliferation of osteoclasts and thus regulates bone metabolism. GPR55 KO mice were also reported to be resistant to mechanical hyperalgesia associated with Freund's complete adjuvant-induced inflammation or partial nerve ligation (
      • Staton P.C.
      • Hatcher J.P.
      • Walker D.J.
      • Morrison A.D.
      • Shapland E.M.
      • Hughes J.P.
      • Chong E.
      • Mander P.K.
      • Green P.J.
      • Billinton A.
      • et al.
      The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain.
      ). In GPR55 KO female mice, the onset of experimentally autoimmune encephalomyelitis was delayed and the symptoms were less severe than those in WT mice (
      • Sisay S.
      • Pryce G.
      • Jackson S.J.
      • Tanner C.
      • Ross R.A.
      • Michael G.J.
      • Selwood D.L.
      • Giovannoni G.
      • Baker D.
      Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis.
      ).
      Now new synthetic ligands selective for GPR55 and GPR55 KO mice are available, and these tools will clearly be helpful in uncovering the true significance of GPR55. Furthermore, emerging data suggest that other endogenous lipid ligands interact with GPR55. For example, N-arachidonoyl serine (ARA-S) and LPG can activate GPR55. Although the most potent known ligand for GPR55 is LPI, it should be kept in mind that some human lysophospholipids have sugar moieties other than inositol. Thus, the possibility that the major ligand of GPR55 is one of these lysophospholipids cannot be ruled out.

      CONCLUSIONS AND FUTURE PROSPECTS

      The LysoGP world has been expanding. In addition to the 11 previously identified GPCRs for LPA and S1P receptors, four GPCRs for LysoPS and one for LPI have been added recently. Now the LysoGP GPCR subfamily has 16 members that specifically react with certain lysophospholipids. However, studies on LysoPS and LPI have just started. We are not really sure if these ligands are physiologically or pathologically relevant. Recent data have shown that LysoPS is produced in vivo in a mouse peritonitis model. Our preliminary data also showed that LysoPS is produced in pathological conditions such as in hepatitis and wound models in mice. These observations suggest that LysoPS is an inflammation-related lipid mediator. However, further studies are needed to determine whether the LysoPS detected in these inflammatory conditions has any roles in the progression of inflammation. For example, studies of the effects of manipulating the genes for the receptors of these LysoGPs especially in the case of LysoPS, will clearly help to understand the pathophysiological roles of LPLs. In addition, we need to identify the enzymes involved in the synthesis of such LPLs. For example, virtually nothing is known about the extracellular production of LPI. GPCRs are highly druggable, i.e., many drugs have been developed. For example, the S1P ligand fingolimod has recently been approved in a number of countries as a treatment for relapsing forms of multiple sclerosis, and an LPA1 antagonist is under clinical testing. The next challenge is to elucidate the pathophysiological roles of these LPLs and to develop drugs that target their receptors.

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