LPA receptor signaling: pharmacology, physiology, and pathophysiology
2014; Elsevier BV; Volume: 55; Issue: 7 Linguagem: Inglês
10.1194/jlr.r046458
ISSN1539-7262
AutoresYun C. Yung, Nicole C. Stoddard, Jerold Chun,
Tópico(s)Lipid Membrane Structure and Behavior
ResumoLysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates medicinal relevance. LPA's functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors are named LPA1–6 and signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs. LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. These studies underscore the potential of LPA receptor subtypes and related signaling mechanisms to provide novel therapeutic targets. Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates medicinal relevance. LPA's functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors are named LPA1–6 and signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs. LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. These studies underscore the potential of LPA receptor subtypes and related signaling mechanisms to provide novel therapeutic targets. Lysophosphatidic acid (LPA) is a small glycerophospholipid (molecular mass: 430–480 Da) that acts as a potent extracellular signaling molecule through at least six cognate G protein-coupled receptors (GPCRs) in numerous developmental and adult processes involving virtually all vertebrate systems. All LPA molecules consist of a glycerol backbone connected to a phosphate head group and are commonly ester-linked to an acyl chain of varied length and saturation. These various chemical forms of LPA are derived from multiple sources, such as membrane lipids (1van Meer G. Voelker D.R. Feigenson G.W. Membrane lipids: where they are and how they behave.Nat. Rev. Mol. Cell Biol. 2008; 9: 112-124Crossref PubMed Scopus (3523) Google Scholar), and exist as bioactive ligands that signal through cognate receptors to produce a wide number of physiological responses (Fig. 1). In the 1960s, studies on smooth muscle and blood pressure hinted at the bioactivity of LPA (2Vogt W. Pharamacologically active acidic phospholipids and glycolipids.Biochem. Pharmacol. 1963; 12: 415-420Crossref PubMed Google Scholar, 3Sen S. Smeby R.R. Bumpus F.M. Antihypertensive effect of an isolated phospholipid.Am. J. Physiol. 1968; 214: 337-341Crossref PubMed Scopus (45) Google Scholar). 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Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex.J. Cell Biol. 1996; 135: 1071-1083Crossref PubMed Google Scholar, 11Chun J. Hla T. Lynch K.R. Spiegel S. Moolenaar W.H. International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature.Pharmacol. Rev. 2010; 62: 579-587Crossref PubMed Scopus (228) Google Scholar). The cloning and functional identification of LPA1 led to the deorphanization of other putative receptor genes based upon sequence homology (12An S. Bleu T. Huang W. Hallmark O.G. Coughlin S.R. Goetzl E.J. Identification of cDNAs encoding two G protein-coupled receptors for lysosphingolipids.FEBS Lett. 1997; 417: 279-282Crossref PubMed Scopus (236) Google Scholar, 13An S. Bleu T. Hallmark O.G. Goetzl E.J. Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid.J. Biol. 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Chem. 1998; 273: 22105-22112Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). At the time of LPA1 identification, the only functional homologous receptor was the cannabinoid receptor CB1 (encoded by CNR1) that interacts with the endogenous lipids anandamide and 2-arachidonoylglycerol (17Devane W.A. Hanus L. Breuer A. Pertwee R.G. Stevenson L.A. Griffin G. Gibson D. Mandelbaum A. Etinger A. Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor.Science. 1992; 258: 1946-1949Crossref PubMed Google Scholar, 18Sugiura T. Kondo S. Sukagawa A. Nakane S. Shinoda A. Itoh K. Yamashita A. Waku K. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain.Biochem. Biophys. Res. Commun. 1995; 215: 89-97Crossref PubMed Scopus (1664) Google Scholar). Two other LPA receptors, LPA2 and LPA3, were subsequently discovered based on shared homology with LPA1. In the past ten years, three additional LPA receptors have been discovered (LPA4–6) (19Noguchi 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; 278: 25600-25606Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar, 20Kotarsky K. Boketoft A. Bristulf J. Nilsson N.E. Norberg A. Hansson S. Owman C. Sillard R. Leeb-Lundberg L.M. Olde B. Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes.J. Pharmacol. Exp. Ther. 2006; 318: 619-628Crossref PubMed Scopus (172) Google Scholar, 21Lee C.W. Rivera R. Gardell S. Dubin A.E. Chun J. GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5.J. Biol. Chem. 2006; 281: 23589-23597Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 22Pasternack S.M. von Kugelgen I. Aboud K.A. Lee Y-A. Ruschendorf F. Voss K. Hillmer A.M. Molderings G.J. Franz T. Ramirez A. et al.G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth.Nat. Genet. 2008; 40: 329-334Crossref PubMed Scopus (301) Google Scholar, 23Yanagida 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; 284: 17731-17741Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar) that are members of the P2Y purinergic family (Fig. 1). These receptors have significantly different encoding sequences than LPA1–3, yet still bind and mediate LPA signaling effects. All six current LPA receptors are class A rhodopsin-like GPCRs with 7-transmembrane (7-TM) domains. Every receptor couples to at least one or more of the four heterotrimeric Gα proteins (G12/13, Gq/11, Gi/o, and Gs) (Fig. 1), resulting in canonical downstream signaling that produces diverse physiological and pathophysiological effects. Other types of lysophospholipids, such as lysophosphatidylserine (LPS), lysophosphatidylinositol, and lysophosphatidylethanolamine (LPE), have some reported bioactivity and are being evaluated for the involvement of possible cognate receptors (24Makide K. Kitamura H. Sato Y. Okutani M. Aoki J. Emerging lysophospholipid mediators, lysophosphatidylserine, lysophosphatidylthreonine, lysophosphatidylethanolamine and lysophosphatidylglycerol.Prostaglandins Other Lipid Mediat. 2009; 89: 135-139Crossref PubMed Scopus (83) Google Scholar). An additional important aspect of LPA receptor biology is that various chemical forms of LPA may differentially activate LPA receptor subtypes (25Kano K. Arima N. Ohgami M. Aoki J. LPA and its analogs-attractive tools for elucidation of LPA biology and drug development.Curr. Med. Chem. 2008; 15: 2122-2131Crossref PubMed Scopus (32) Google Scholar). This finding has been supported by secondary readouts of receptor activity, because direct confirmation through classical receptor binding studies has been difficult. There are two major synthetic pathways for LPA. In the first pathway, the precursor phospholipids (phosphatidylcholine, phosphatidylserine, or phosphatidylethanolamine) can be converted to their corresponding lysophospholipids such as lysophosphatidylcholine (LPC), LPS, or LPE. In platelets, this occurs via phosphatidylserine-specific phospholipase A1 (PS-PLA1) or secretory phospholipase A2 (sPLA2) activity. In plasma, LPC is produced by LCAT and PLA1 activity. In either location, lysophospholipids can then be converted to LPA via autotaxin (ATX) activity (Fig. 1). In the second major pathway, phosphatidic acid (PA) is first produced from phospholipids through phospholipase D or from diacylglycerol through diacylglycerol kinase. Then, PA is converted directly to LPA by the actions of either PLA1 or PLA2 (26Aoki J. Inoue A. Okudaira S. Two pathways for lysophosphatidic acid production.Biochim. Biophys. Acta. 2008; 1781: 513-518Crossref PubMed Scopus (294) Google Scholar) (Fig. 1). Through a separate mechanism, LPA can be generated through the acylation of glycerol-3-phosphate by glycerophosphate acyltransferase and the phosphorylation of monoacylglycerol by monoacylglycerol kinase (27Bektas M. Payne S.G. Liu H. Goparaju S. Milstien S. Spiegel S. A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells.J. Cell Biol. 2005; 169: 801-811Crossref PubMed Scopus (131) Google Scholar). Additional LPA-producing pathways also exist (26Aoki J. Inoue A. Okudaira S. Two pathways for lysophosphatidic acid production.Biochim. Biophys. Acta. 2008; 1781: 513-518Crossref PubMed Scopus (294) Google Scholar, 28Pagès C. Simon M-F. Valet P. Saulnier-Blache J.S. Lysophosphatidic acid synthesis and release.Prostaglandins Other Lipid Mediat. 2001; 64: 1-10Crossref PubMed Scopus (145) Google Scholar). LPA generation from membrane phospholipids occurs in both intracellular and extracellular fashions (28Pagès C. Simon M-F. Valet P. Saulnier-Blache J.S. Lysophosphatidic acid synthesis and release.Prostaglandins Other Lipid Mediat. 2001; 64: 1-10Crossref PubMed Scopus (145) Google Scholar). Intracellular LPA is an important intermediate for the de novo biosynthesis of complex glycerolipids, including mono-, di-, and triglycerides, as well as phospholipids (28Pagès C. Simon M-F. Valet P. Saulnier-Blache J.S. Lysophosphatidic acid synthesis and release.Prostaglandins Other Lipid Mediat. 2001; 64: 1-10Crossref PubMed Scopus (145) Google Scholar). 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The term LPA most often refers to 18:1 oleoyl-LPA (1-acyl-2-hydroxy-sn-glycero-3-phosphate), as it is the most commonly used laboratory species. However, there is a growing range of recognized chemical forms of LPA in various biological systems (31Aoki J. Mechanisms of lysophosphatidic acid production.Semin. Cell Dev. Biol. 2004; 15: 477-489Crossref PubMed Scopus (226) Google Scholar, 32Sugiura T. Nakane S. Kishimoto S. Waku K. Yoshioka Y. Tokumura A. Hanahan D.J. Occurrence of lysophosphatidic acid and its alkyl ether-linked analog in rat brain and comparison of their biological activities toward cultured neural cells.Biochim. Biophys. Acta. 1999; 1440: 194-204Crossref PubMed Scopus (88) Google Scholar) that have been observed in concentrations spanning low nanomolar to micromolar levels. LPA concentrations in blood can range from 0.1 μM in plasma and up to 10 μM in serum, which is well over the apparent nanomolar Kd of LPA1–6 (23Yanagida 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; 284: 17731-17741Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 33Aoki 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.J. Biol. Chem. 2002; 277: 48737-48744Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 34Hosogaya S. Yatomi Y. Nakamura K. Ohkawa R. Okubo S. Yokota H. Ohta M. Yamazaki H. Koike T. Ozaki Y. Measurement of plasma lysophosphatidic acid concentration in healthy subjects: strong correlation with lysophospholipase D activity.Ann. Clin. Biochem. 2008; 45: 364-368Crossref PubMed Scopus (54) Google Scholar, 35Watanabe N. Ikeda H. Nakamura K. Ohkawa R. Kume Y. Aoki J. Hama K. Okudaira S. Tanaka M. 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Plasma lysophosphatidic acid levels and hepatocellular carcinoma.Hepatology. 2013; 57: 417-418Crossref PubMed Scopus (5) Google Scholar).TABLE 1Summary of LPA concentrations in various tissues and biological fluidsTissues/FluidsLPALPCMethod of MeasurementReferencesPhysiological conditionsEmbryonic brain0.32–0.35 pmol/mgaValues from nonhuman organisms.Not availableLC-MS(43Yung Y.C. Mutoh T. Lin M.E. Noguchi K. Rivera R.R. Choi J.W. Kingsbury M.A. Chun J. Lysophosphatidic acid signaling may initiate fetal hydrocephalus.Sci. Transl. Med. 2011; 3: 99ra87Crossref PubMed Scopus (94) Google Scholar)Adult brain3.7–35 pmol/mgaValues from nonhuman organisms.Not availableGC-MS, LC-MS/MS(32Sugiura T. Nakane S. Kishimoto S. Waku K. Yoshioka Y. Tokumura A. Hanahan D.J. Occurrence of lysophosphatidic acid and its alkyl ether-linked analog in rat brain and comparison of their biological activities toward cultured neural cells.Biochim. Biophys. 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Biophys. 2002; 402: 51-58Crossref PubMed Scopus (74) Google Scholar)Nerve (spinal cord)0.79 pmol/mgaValues from nonhuman organisms.Not availableB103 bioassay(42Ma L. Uchida H. Nagai J. Inoue M. Aoki J. Ueda H. Evidence for de novo synthesis of lysophosphatidic acid in the spinal cord through phospholipase A2 and autotaxin in nerve injury-induced neuropathic pain.J. Pharmacol. Exp. Ther. 2010; 333: 540-546Crossref PubMed Scopus (56) Google Scholar)Plasma0.7 μMbValues from humans./0.17–0.63 μMaValues from nonhuman organisms.100-140 μMbValues from humans./440 μMaValues from nonhuman organisms.LC-MS, RH7777 bioassay(38Scherer M. Schmitz G. Liebisch G. High-throughput analysis of sphingosine 1-phosphate, sphinganine 1-phosphate, and lysophosphatidic acid in plasma samples by liquid chromatography-tandem mass spectrometry.Clin. Chem. 2009; 55: 1218-1222Crossref PubMed Scopus (112) Google Scholar, 239Tokumura A. Carbone L.D. Yoshioka Y. Morishige J. Kikuchi M. Postlethwaite A. Watsky M.A. Elevated serum levels of arachidonoyl-lysophosphatidic acid and sphingosine-1-phosphate in systemic sclerosis.Int. J. Med. Sci. 2009; 6: 168-176Crossref PubMed Google Scholar, 299Yamada T. Sato K. Komachi M. Malchinkhuu E. Tobo M. Kimura T. Kuwabara A. Yanagita Y. Ikeya T. Tanahashi Y. et al.Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1.J. Biol. Chem. 2004; 279: 6595-6605Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 341Barber M.N. Risis S. Yang C. Meikle P.J. Staples M. Febbraio M.A. Bruce C.R. Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes.PLoS ONE. 2012; 7: e41456Crossref PubMed Scopus (183) Google Scholar)Serum4–15.5 μMbValues from humans.234 μMbValues from humans.TLC-GC, enzymatic assay, LC-MS/MS(166Tokumura A. Miyake M. Nishioka Y. Yamano S. Aono T. Fukuzawa K. Production of lysophosphatidic acids by lysophospholipase D in human follicular fluids of in vitro fertilization patients.Biol. Reprod. 1999; 61: 195-199Crossref PubMed Scopus (111) Google Scholar, 342Kishimoto T. Soda Y. Matsuyama Y. Mizuno K. An enzymatic assay for lysophosphatidylcholine concentration in human serum and plasma.Clin. Biochem. 2002; 35: 411-416Crossref PubMed Scopus (71) Google Scholar, 343Cho W.H. Park T. Park Y.Y. Huh J.W. Lim C.M. Koh Y. Song D.K. Hong S.B. Clinical significance of enzymatic lysophosphatidylcholine (LPC) assay data in patients with sepsis.Eur. J. Clin. Microbiol. Infect. Dis. 2012; 31: 1805-1810Crossref PubMed Scopus (0) Google Scholar)CSF0.025–0.2 pMaValues from nonhuman organisms.Not detectedaValues from nonhuman organisms.RH7777 bioassay(344Sato K. Malchinkhuu E. Muraki T. Ishikawa K. Hayashi K. Tosaka M. Mochiduki A. Inoue K. Tomura H. Mogi C. et al.Identification of autotaxin as a neurite retraction-inducing factor of PC12 cells in cerebrospinal fluid and its possible sources.J. Neurochem. 2005; 92: 904-914Crossref PubMed Scopus (62) Google Scholar)Seminal fluidNegligible8–19 μMbValues from humans.RH7777 bioassay, enzymatic cycling(41Tanaka M. Kishi Y. Takanezawa Y. Kakehi Y. Aoki J. Arai H. Prostatic acid phosphatase degrades lysophosphatidic acid in seminal plasma.FEBS Lett. 2004; 571: 197-204Crossref PubMed Scopus (91) Google Scholar)Saliva0.785 nMbValues from humans.Not availableFAB-MS(345Sugiura T. Nakane S. Kishimoto S. Waku K. Yoshioka Y. Tokumura A. Lysophosphatidic acid, a growth factor-like lipid, in the saliva.J. Lipid Res. 2002; 43: 2049-2055Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar)Lacrimal gland fluid1.3 μMaValues from nonhuman organisms.Not availableMS(45Liliom K. Guan Z. Tseng J.L. Desiderio D.M. Tigyi G. 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