Lysophospholipid G Protein-coupled Receptors
2004; Elsevier BV; Volume: 279; Issue: 20 Linguagem: Inglês
10.1074/jbc.r400013200
ISSN1083-351X
AutoresBrigitte Anliker, Jerold Chun,
Tópico(s)Lipid metabolism and biosynthesis
ResumoThe many biological responses documented for lysophospholipids that include lysophosphatidic acid and sphingosine 1-phosphate can be mechanistically attributed to signaling through specific G protein-coupled receptors. At least nine receptors have now been identified, and the total number is likely to be larger. In this brief review, we note cogent features of lysophospholipid receptors, including the current nomenclature, signaling properties, development of agonists and antagonists, and physiological functions. The many biological responses documented for lysophospholipids that include lysophosphatidic acid and sphingosine 1-phosphate can be mechanistically attributed to signaling through specific G protein-coupled receptors. At least nine receptors have now been identified, and the total number is likely to be larger. In this brief review, we note cogent features of lysophospholipid receptors, including the current nomenclature, signaling properties, development of agonists and antagonists, and physiological functions. The increasingly well studied lysophospholipids (LPs) 1The abbreviations used are: LP, lysophospholipid; LPA, lysophosphatidic acid; S1P, sphingosine 1-phosphate; GPCR, G protein-coupled receptor; SPC, sphingosylphosphorylcholine; aa, amino acids; MEF, mouse embryonic fibroblast; AC, adenylyl cyclase; PLC, phospholipase C. known as lysophosphatidic acid or LPA (1Moolenaar W.H. J. Biol. Chem. 1995; 270: 12949-12952Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar, 2Tokumura A. Biochim. Biophys. Acta. 2002; 1582: 18-25Crossref PubMed Scopus (88) Google Scholar, 3Mills G.B. Moolenaar W.H. Nat. Rev. Cancer. 2003; 3: 582-591Crossref PubMed Scopus (963) Google Scholar, 4Tigyi G. Parrill A.L. Prog. Lipid Res. 2003; 42: 498-526Crossref PubMed Scopus (157) Google Scholar, 5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar) and sphingosine 1-phosphate or S1P (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar, 6Spiegel S. Olivera A. Zhang H. Thompson E.W. Su Y. Berger A. Breast Cancer Res. Treat. 1994; 31: 337-348Crossref PubMed Scopus (41) Google Scholar) (Fig. 1) have garnered interest for their extracellular signaling properties. It is now clear that a majority of the responses documented for extracellular LPs is attributable to the activation of specific, seven-transmembrane domain G protein-coupled receptors (GPCRs). There are currently nine distinct LP receptors, four of which mediate effects of LPA and five that mediate effects of S1P (Table I). These receptors have been known by many different orphan receptor names, which recently led to a consensus, receptor renaming, based upon the identity of high affinity ligands (7Chun J. Goetzl E.J. Hla T. Igarashi Y. Lynch K.R. Moolenaar W. Pyne S. Tigyi G. Pharmacol. Rev. 2002; 54: 265-269Crossref PubMed Scopus (452) Google Scholar): the LPA receptors consisting of LPA1–4 and S1P receptors consisting of S1P1–5 (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar, 8Fukushima N. Ishii I. Contos J.J. Weiner J.A. Chun J. Annu. Rev. Pharmacol. Toxicol. 2001; 41: 507-534Crossref PubMed Scopus (328) Google Scholar, 9Hla T. Pharmacol. Res. 2003; 47: 401-407Crossref PubMed Scopus (242) Google Scholar). Genetic nulls (Table II) have driven a number of recent analyses toward understanding physiological functions (see Fig. 3).Table ILysophospholipid receptorsReceptoraThe current receptor nomenclature follows the guidelines of the International Union for Pharmacology (IUPHAR).SynonymsLigandsAgonistsAntagonistsLPA1VGZ-1LPA (high affinity)Several NAEPA derivativesSuramin (low specificity); DGPP 8:0 and PA 8:0 (weak antagonists); Ki16425; FAP-12 (weak antagonist); VPC12249EDG-2mrec1.3GPCR 26LPA1LPA2EDG-4(non-mutant)LPA (Kd = 73.6 nm)Several NAEPA derivatives; FAP-10; FAP-12LPA2LPA3EDG-7LPA (Kd = 206 nm)Several NAEPA derivatives; OMPT; a monofluorinated analog of LPADGPP 8:0; PA 8:0; Ki16425; FAP-12; VPC12249LPA3LPA4P2Y9LPA (Kd = 45 nm)GPR23S1P1EDG-1S1P (Kd = 8-13 nm); dh-S1P; SPC (low affinity)FTY720 and an analog, (R)-AAL, after phosphorylation to FTY720-P (Compound A) and (R)-AFD; SEW2871LPB1S1P2AGR16S1P (Kd = 20-27 nm); dh-S1P; SPC (low affinity)Pyrozolopyridine derivative named JTE-013H218EDG-5LPB2S1P3EDG-3S1P (Kd = 23-26 nm); dh-S1P; SPC (low affinity)FTY720-P (Compound A) and (R)-AFDSuraminLPB3S1P4EDG-6PhS1P (Kd = 1.6 nm)FTY720-P (Compound A) and (R)-AFDLPC1S1P (Kd = 13-63 nm); dh-S1P; SPC (low affinity)S1P5NRG-1S1P (Kd = 2-10 nm); dh-S1P; SPC (low affinity)FTY720-P (Compound A) and (R)-AFDEDG-8LPB4a The current receptor nomenclature follows the guidelines of the International Union for Pharmacology (IUPHAR). Open table in a new tab Table IIPhenotypes of reported LP receptor-null miceReceptor deletedViability and fertilityPhenotypeCellular signalingLPA1Semi-lethal, fertileImpaired suckling behavior; decreased postnatal growth rate; reduced size; craniofacial dysmorphism; low incidence of frontal hematoma (2.5%); increased apoptosis of Schwann cells in the sciatic nerveImpaired cluster compaction and decreased cell proliferation of dissociated embryonic LPA1-/- neuroblasts in response to LPA; reduced PLC activation and Ca2+ mobilization and abolished AC inhibition in MEFs following LPA stimulationLPA2Viable, fertileNo major phenotypeReduced PLC activation and Ca2+ mobilization in MEFs after stimulation with LPALPA1/LPA2Semi-lethal, fertilePhenotype comparable with LPA1-/- mice with a higher incidence of frontal hematoma (26%); no alterations in cell proliferation, histology, or thickness of cerebral cortices; apoptosis in sciatic nerve was not analyzedAbolished PLC activation and Ca2+ mobilization, abolished AC inhibition, severely reduced stress fiber formation, abolished activation of JNK and Akt as well as abolished proliferative response of MEFs to LPAS1P1LethalEmbryonic hemorrhage; intrauterine death between E12.5 and E14.5; impaired recruitment of VSMCs to blood vessels; defective ensheathment and maturation of vesselsSeverely reduced migratory response of MEFs to S1PS1P2Viable, slightly reduced fertilityApparently normal or seizures between 3 and 7 weeks of age on mixed genetic background; no anatomical defects; neuronal hyperexcitabilitySignificant decrease of S1P- induced Rho activation in MEFsS1P3Viable, slightly reduced fertilityNo major phenotypeDecreased PLC activation and slightly decreased AC inhibition in MEFs following S1P stimulationS1P2/S1P3Reduced viability, severely reduced fertilityReduced fertilityComplete loss of Rho activation and decrease in PLC activation in MEFs stimulated with S1P Open table in a new tab Fig. 3Biological roles of lysophospholipids in different systems. Receptor-mediated cellular responses to LPA and S1P, such as survival, proliferation, and migration, exhibit biological significance particularly within the nervous system, the cardiovascular system, the immune system, and the female reproductive system. Indicated are physiological and pathophysiological functions of LPA and S1P and the involved receptors. IL-2, interleukin-2; OCCs, ovarian cancer cells; SCs, Schwann cells; VEC, vascular endothelial cells; VSMCs, vascular smooth muscle cells; HDL, high density lipoprotein.View Large Image Figure ViewerDownload (PPT) In addition to these proven receptors, an enlarging number of orphan receptors have been provisionally identified as LP receptors; however, in many cases conflicting data exist on their identity. In particular, some putative receptors for sphingosylphosphorylcholine (SPC) and lysophosphatidylcholine (LPC) (10Xu Y. Biochim. Biophys. Acta. 2002; 1582: 81-88Crossref PubMed Scopus (201) Google Scholar) may in fact be proton sensors, unrelated to LP signaling (11Ludwig M.-G. Vanek M. Guerini D. Gasser J.A. Jones C.E. Junker U. Hofstetter H. Wolf R.M. Seuwen K. Nature. 2003; 425: 94-98Crossref Scopus (546) Google Scholar); these and other orphan/putative LP receptors are reviewed elsewhere (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar). Similarly, no attempt is made to cover the important developments in understanding LP biochemistry and metabolism, which have been the subject of many excellent reviews (3Mills G.B. Moolenaar W.H. Nat. Rev. Cancer. 2003; 3: 582-591Crossref PubMed Scopus (963) Google Scholar, 5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar, 12Osborne N. Stainier D.Y. Annu. Rev. Physiol. 2003; 65: 23-43Crossref PubMed Scopus (35) Google Scholar, 13Spiegel S. Milstien S. Nat. Rev. Mol. Cell. Biol. 2003; 4: 397-407Crossref PubMed Scopus (1791) Google Scholar, 14Xie Y. Gibbs T.C. Meier K.E. Biochim. Biophys. Acta. 2002; 1582: 270-281Crossref PubMed Scopus (66) Google Scholar, 15Pages C. Simon M.F. Valet P. Saulnier-Blache J.S. Prostaglandins Other Lipid Mediat. 2001; 64: 1-10Crossref PubMed Scopus (165) Google Scholar, 16Yatomi Y. Ozaki Y. Ohmori T. Igarashi Y. Prostaglandins. 2001; 64: 107-122Crossref PubMed Scopus (168) Google Scholar, 17Okajima F. Biochim. Biophys. Acta. 2002; 1582: 132-137Crossref PubMed Scopus (209) Google Scholar, 18Meyer zu Heringdorf D. Himmel H.M. Jakobs K.H. Biochim. Biophys. Acta. 2002; 1582: 178-189Crossref PubMed Scopus (124) Google Scholar, 19Kluk M.J. Hla T. Biochim. Biophys. Acta. 2002; 1582: 72-80Crossref PubMed Scopus (281) Google Scholar, 20Siehler S. Manning D.R. Biochim. Biophys. Acta. 2002; 1582: 94-99Crossref PubMed Scopus (115) Google Scholar, 21Takuwa Y. Biochim. Biophys. Acta. 2002; 1582: 112-120Crossref PubMed Scopus (155) Google Scholar). In this minireview, with apologies to many colleagues for citation limits, we highlight major features of LPA and S1P GPCRs. There are four identified LPA receptors in mammals (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar). A distinct gene encodes each receptor that activates downstream signaling pathways mediated by one or more G proteins (Tables I and II; Figs. 2 and 3). The first three, LPA1–3, share sequence homology with one another, whereas LPA4 is divergent in sequence. LPA1 represents the first LP receptor identified. In mice, a multi-exon gene structure was reported, with the coding region characterized by conservation of a single intron separating two coding regions at the sixth transmembrane domain. This intronic structure is shared with lpa2 and lpa3. LPA1 contains 364 amino acids (aa) in a seven-transmembrane receptor structure, with an apparent molecular mass of ∼41 kDa. LPA1 couples to multiple G proteins (Fig. 2). In both humans and mouse, adult expression is widespread and includes most major tissues. However, within a single tissue, heterogeneity of cell types expressing lpa1 also exists. Targeted deletion of lpa1 revealed ∼50% perinatal lethality in a mixed background strain (Table II). Remaining survivors showed reduced body mass and head/facial deformity and increased cell death of Schwann cells. Postnatal lethality was in part related to suckling problems associated with olfactory defects, whereas exencephaly and frontal brain hemorrhage likely contributed to a small proportion of embryonic loss. LPA signaling was lost or vastly decreased in mouse embryonic fibroblasts (MEFs) and cerebral cortical neuroprogenitor cells. Independent deletion of LPA1 in mice has been associated with behavioral changes reminiscent of psychiatric disorders (22Harrison S.M. Reavill C. Brown G. Brown J.T. Cluderay J.E. Crook B. Davies C.H. Dawson L.A. Grau E. Heidbreder C. Hemmati P. Hervieu G. Howarth A. Hughes Z.A. Hunter A.J. Latcham J. Pickering S. Pugh P. Rogers D.C. Shilliam C.S. Maycox P.R. Mol. Cell Neurosci. 2003; 24: 1170-1179Crossref PubMed Scopus (111) Google Scholar). Key roles in cell migration have been recently described (23Hama K. Aoki J. Fukaya M. Kishi Y. Sakai T. Suzuki R. Ohta H. Yamori T. Watanabe M. Chun J. Arai H. J. Biol. Chem. 2004; 279: 17634-17639Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar) as well as surprising effects on the formation of the central nervous system (Fig. 3) (24Kingsbury M.A. Rehen S.K. Contos J.J.A. Higgins C.M. Chun J. Nat. Neurosci. 2003; 6: 1292-1299Crossref PubMed Scopus (213) Google Scholar). LPA2 was the second LPA receptor identified. A mutant variant named EDG-4 is absent from wild-type genomes and is therefore not synonymous with LPA2. Gene structure analyses reveal the conserved intron in transmembrane domain 6. LPA2 contains 351 aa (human) or 348 aa (mouse) with a predicted molecular mass of ∼39 kDa. LPA2 also couples with multiple forms of G proteins (Fig. 2) and shows widespread adult tissue expression in humans and mouse. It has been detected in various cancer cell lines, and variants within the 3′-untranslated region exist. Targeted genetic nulls of lpa2 do not have blatant phenotypes yet do show defects and/or loss of wild-type LPA signaling in MEFs (Table II). Double mutants of lpa1(–/–) and lpa2(–/–) show MEF defects in most LPA-related signaling (e.g. AC inhibition, c-Jun N-terminal kinase and Akt activation, PLC activation, Ca2+ mobilization, stress fiber formation, and cell proliferation). The dual elimination of both receptors has also revealed involvement in central nervous system development (24Kingsbury M.A. Rehen S.K. Contos J.J.A. Higgins C.M. Chun J. Nat. Neurosci. 2003; 6: 1292-1299Crossref PubMed Scopus (213) Google Scholar). LPA3 also has a gene structure containing the conserved intron in transmembrane domain 6. It contains 353 aa (human) and 354 aa (mouse), with a predicted molecular mass of ∼40 kDa. It differs from the other previous two LPA receptors by not coupling to G12/13 (Fig. 2) and showing a preference for LPA molecules with unsaturated acyl chains. Although still expressed in many adult tissues, it shows somewhat more restricted expression (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar). Its signaling properties are generally similar to LPA1 and LPA2 except for AC-related effects that vary with respect to analyzed cell lines. Targeted deletions have not yet been reported. LPA4 (25Noguchi K. Ishii S. Shimizu T. J. Biol. Chem. 2003; 278: 25600-25606Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar) was the first LPA receptor with a divergent sequence that shows greater similarity to the platelet-activating factor GPCR. Comparatively less is known about this receptor. It appears to be encoded on a single exon, and both human and mouse receptors contain 370 aa with a molecular mass of ∼42 kDa. Gene expression is most marked in the ovaries but is also observed at lower levels in several other tissues. Biological roles, null mutations, and its relationship to the other LPA receptors have not been reported. There are five identified S1P receptors in mammals (Tables I and II; Figs. 2 and 3) (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar, 9Hla T. Pharmacol. Res. 2003; 47: 401-407Crossref PubMed Scopus (242) Google Scholar, 13Spiegel S. Milstien S. Nat. Rev. Mol. Cell. Biol. 2003; 4: 397-407Crossref PubMed Scopus (1791) Google Scholar, 26Pyne S. Pyne N.J. Biochim. Biophys. Acta. 2002; 1582: 121-131Crossref PubMed Scopus (81) Google Scholar). The first receptor identified was S1P1 (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar, 8Fukushima N. Ishii I. Contos J.J. Weiner J.A. Chun J. Annu. Rev. Pharmacol. Toxicol. 2001; 41: 507-534Crossref PubMed Scopus (328) Google Scholar, 27Lee M.J. Van Brocklyn J.R. Thangada S. Liu C.H. Hand A.R. Menzeleev R. Spiegel S. Hla T. Science. 1998; 279: 1552-1555Crossref PubMed Scopus (896) Google Scholar, 28Van Brocklyn J.R. Lee M.J. Menzeleev R. Olivera A. Edsall L. Cuvillier O. Thomas D.M. Coopman P.J. Thangada S. Liu C.H. Hla T. Spiegel S. J. Cell Biol. 1998; 142: 229-240Crossref PubMed Scopus (450) Google Scholar), and it is also the best characterized S1P receptor. Unlike most LPA receptors it is encoded within a single exon, and this gene structure is shared by all five S1P receptors. Both human and mouse receptors contain 382 aa with an apparent molecular mass of ∼43 kDa. As with the LPA receptors, it has wide adult tissue expression and interacts with Gi proteins (Fig. 2). It also shows responses that are related to platelet-derived growth factor signaling, because platelet-derived growth factor-induced effects are perturbed in s1p1(–/–) MEFs. The null genotype of s1p1 was embryonic lethal (29Liu Y. Wada R. Yamashita T. Mi Y. Deng C.X. Hobson J.P. Rosenfeldt H.M. Nava V.E. Chae S.S. Lee M.J. Liu C.H. Hla T. Spiegel S. Proia R.L. J. Clin. Invest. 2000; 106: 951-961Crossref PubMed Scopus (1009) Google Scholar) with death attributable to incomplete vascular maturation (Table II). Conditional deletion studies demonstrate that vascular endothelial cells are the primary target for the actions of S1P1 loss (30Allende M.L. Yamashita T. Proia R.L. Blood. 2003; 102: 3665-3667Crossref PubMed Scopus (322) Google Scholar) (Fig. 3). Recent reports demonstrate specific roles for S1P1 in lymphocyte recirculation/egress (31Sanna M.G. Liao J. Jo E. Alfonso C. Ahn M.Y. Peterson M.S. Webb B. Lefebvre S. Chun J. Gray N. Rosen H. J. Biol. Chem. 2004; 279: 13839-13848Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar, 32Matloubian M. Lo C.G. Cinamon G. Lesneski M.J. Xu Y. Brinkmann V. Allende M.L. Proia R.L. Cyster J.G. Nature. 2004; 427: 355-360Crossref PubMed Scopus (2137) Google Scholar). S1P2 is encoded on a single exon and contains 353 aa (human) and 352 aa (mouse) with an apparent molecular mass of ∼39 kDa. It shows widespread tissue distribution and couples with multiple G proteins (Fig. 2). Genetic deletion of an apparent zebra fish s1p2 orthologue (33Kupperman E. An S. Osborne N. Waldron S. Stainier D.Y. Nature. 2000; 406: 192-195Crossref PubMed Scopus (351) Google Scholar) revealed developmental heart defects although an analogous phenotype was not observed in independent deletions of s1p2 in mice (34MacLennan A.J. Carney P.R. Zhu W.J. Chaves A.H. Garcia J. Grimes J.R. Anderson K.J. Roper S.N. Lee N. Eur. J. Neurosci. 2001; 14: 203-209Crossref PubMed Google Scholar, 35Ishii I. Ye X. Friedman B. Kawamura S. Contos J.J. Kingsbury M.A. Yang A.H. Zhang G. Brown J.H. Chun J. J. Biol. Chem. 2002; 277: 25152-25159Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). In mice, s1p2(–/–) genotype demonstrated MEF signaling defects for Rho activation (Table II). Although appearing grossly normal, some nulls revealed sporadic and at times lethal seizures in a neuroanatomically normal setting that may be related to increased excitability in neocortical pyramidal neurons (34MacLennan A.J. Carney P.R. Zhu W.J. Chaves A.H. Garcia J. Grimes J.R. Anderson K.J. Roper S.N. Lee N. Eur. J. Neurosci. 2001; 14: 203-209Crossref PubMed Google Scholar). By comparison, other s1p2(–/–) mice did not show seizure activity but did exhibit decreased litter size (35Ishii I. Ye X. Friedman B. Kawamura S. Contos J.J. Kingsbury M.A. Yang A.H. Zhang G. Brown J.H. Chun J. J. Biol. Chem. 2002; 277: 25152-25159Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar); the reasons for these differences may reflect background strain effects. S1P3 is also encoded on a single exon, and both human and mouse receptors contain 378 aa residues with an apparent molecular mass of ∼42 kDa. It shows wide tissue distribution in humans and mouse. It also couples to multiple G proteins (Fig. 2). Gene targeting revealed no gross abnormalities aside from a slightly decreased litter size (Table II). By contrast, MEF S1P signaling was notably affected, particularly PLC activation and Ca2+ mobilization in contrast to normal Rho activation and inhibition of AC. Double null s1p2(–/–)s1p3(–/–) mice (35Ishii I. Ye X. Friedman B. Kawamura S. Contos J.J. Kingsbury M.A. Yang A.H. Zhang G. Brown J.H. Chun J. J. Biol. Chem. 2002; 277: 25152-25159Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar) have markedly reduced litter sizes and low survival beyond postnatal week 3. Loss of both receptors eliminates S1P-dependent Rho activation in MEFs. Bradycardia that is mediated by this receptor has recently been reported (Fig. 3) (31Sanna M.G. Liao J. Jo E. Alfonso C. Ahn M.Y. Peterson M.S. Webb B. Lefebvre S. Chun J. Gray N. Rosen H. J. Biol. Chem. 2004; 279: 13839-13848Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar). S1P4 is again found encoded on a single exon. It contains 384 aa (human) and 386 aa (mouse) with an apparent molecular mass of ∼42 kDa. It has relatively low amino acid sequence similarity to the other S1P receptors suggesting that it might prefer a distinct ligand (8Fukushima N. Ishii I. Contos J.J. Weiner J.A. Chun J. Annu. Rev. Pharmacol. Toxicol. 2001; 41: 507-534Crossref PubMed Scopus (328) Google Scholar); indeed phytosphingosine 1-phosphate (4d-hydroxysphinganine 1-phosphate) appears to be such a ligand (36Candelore M.R. Wright M.J. Tota L.M. Milligan J. Shei G.J. Bergstrom J.D. Mandala S.M. Biochem. Biophys. Res. Commun. 2002; 297: 600-606Crossref PubMed Scopus (49) Google Scholar). Unlike other S1P receptors its expression pattern is predominantly in lymphoid compartments. S1P4 couples with multiple G proteins (Fig. 2). Targeted deletion of this receptor has not been reported. S1P5 retains a single exon coding region (8Fukushima N. Ishii I. Contos J.J. Weiner J.A. Chun J. Annu. Rev. Pharmacol. Toxicol. 2001; 41: 507-534Crossref PubMed Scopus (328) Google Scholar). It contains 398 aa (human) and 400 aa (mouse) and has an apparent molecular mass of ∼42 kDa. It couples to multiple G proteins (Fig. 2) and shows intermediate expression levels compared with the previously mentioned receptors having notable expression in rat brain where it is expressed in white matter tracts and oligodendrocytes. In contrast to other S1P receptors it appears to inhibit mitogen-activated protein kinase activation. Genetic nulls have not yet been reported. Important tools for the study of GPCRs are appropriate agonists and antagonists (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar, 37Lynch K.R. Macdonald T.L. Biochim. Biophys. Acta. 2002; 1582: 289-294Crossref PubMed Scopus (43) Google Scholar). It is notable that many reported compounds have not been adequately validated in a range of assays or in vivo. Nevertheless, a number of promising compounds have entered the experimental literature (Table I). Examples of LPA-related compounds (37Lynch K.R. Macdonald T.L. Biochim. Biophys. Acta. 2002; 1582: 289-294Crossref PubMed Scopus (43) Google Scholar) include Ki16425, an LPA1 and LPA3 antagonist (38Ohta H. Sato K. Murata N. Daminin A. Malchinkhuu E. Kon J. Kimura T. Tobo M. Yamazaki Y. Watanabe T. Yagi M. Sato M. Suzuki R. Murooka H. Sakai T. Nishitoba T. Im D.S. Nochi H. Tamoto K. Tomura H. Okajima T. Mol. Pharmacol. 2003; 64: 994-1005Crossref PubMed Scopus (340) Google Scholar); an ethanolamide derivative (VPC12249) with LPA1 and LPA3 antagonist actions (37Lynch K.R. Macdonald T.L. Biochim. Biophys. Acta. 2002; 1582: 289-294Crossref PubMed Scopus (43) Google Scholar); decyl and dodecyl fatty alcohol phosphates referred to as FAP-10 and FAP-12 that can act as LPA2 agonists (41Virag T. Elrod D.B. Liliom K. Sardar V.M. Parrill A.L. Yokoyama K. Durgam G. Deng W. Miller D.D. Tigyi G. Mol. Pharmacol. 2003; 63: 1032-1042Crossref PubMed Scopus (71) Google Scholar); a phosphothionate analog of LPA (OMPT) that shows LPA3 agonism (42Hasegawa Y. Erickson J.R. Goddard G.J. Yu S. Liu S. Cheng K.W. Eder A. Bandoh K. Aoki J. Jarosz R. Schrier A.D. Lynch K.R. Mills G.B. Fang X. J. Biol. Chem. 2003; 278: 11962-11969Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar); a monofluorinated analog of LPA also showing LPA3 agonism (43Xu Y. Qian L. Prestwich G.D. J. Org. Chem. 2003; 68: 5320-5330Crossref PubMed Scopus (68) Google Scholar); a diacylglycerol pyrophosphate (DGPP 8:0), which shows LPA3 antagonism (40Sardar V.M. Bautista D.L. Fischer D.J. Yokoyama K. Nusser N. Virag T. Wang D.A. Baker D.L. Tigyi G. Parrill A.L. Biochim. Biophys. Acta. 2002; 1582: 309-317Crossref PubMed Scopus (78) Google Scholar, 44Fischer D.J. Nusser N. Virag T. Yokoyama K. Wang D.A. Baker D.L. Bautista D. Parrill A.L. Tigyi G. Mol. Pharmacol. 2001; 60: 776-784PubMed Google Scholar); a fluoromethyl-phenyl oxadiazole (SEW2871) that shows S1P1 selective agonism (31Sanna M.G. Liao J. Jo E. Alfonso C. Ahn M.Y. Peterson M.S. Webb B. Lefebvre S. Chun J. Gray N. Rosen H. J. Biol. Chem. 2004; 279: 13839-13848Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar); and a pyrazolopyridine (JTE-013) showing S1P2 antagonism (45Osada M. Yatomi Y. Ohmori T. Ikeda H. Ozaki Y. Biochem. Biophys. Res. Commun. 2002; 299: 483-487Crossref PubMed Scopus (178) Google Scholar). The best validated in vivo compound is the pro-drug FTY720 that shows non-selective agonism of several S1P receptors following its phosphorylation into an active species (46Mandala S. Hajdu R. Bergstrom J. Quackenbush E. Xie J. Milligan J. Thornton R. Shei G.J. Card D. Keohane C. Rosenbach M. Hale J. Lynch C.L. Rupprecht K. Parsons W. Rosen H. Science. 2002; 296: 346-349Crossref PubMed Scopus (1466) Google Scholar, 47Brinkmann V. Davis M.D. Heise C.E. Albert R. Cottens S. Hof R. Bruns C. Prieschl E. Baumruker T. Hiestand P. Foster C.A. Zollinger M. Lynch K.R. J. Biol. Chem. 2002; 277: 21453-21457Abstract Full Text Full Text PDF PubMed Scopus (1343) Google Scholar). LP signaling through GPCRs has major influences on multiple organ systems, and an increased understanding of the physiological and pathophysiological effects of LPs is perhaps the major growth area in this field (3Mills G.B. Moolenaar W.H. Nat. Rev. Cancer. 2003; 3: 582-591Crossref PubMed Scopus (963) Google Scholar, 5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar, 48Karliner J.S. Biochim. Biophys. Acta. 2002; 1582: 216-221Crossref PubMed Scopus (79) Google Scholar, 49Goetzl E.J. Graeler M. Huang M.C. Shankar G. Sci. World J. 2002; 2: 324-338Crossref Scopus (31) Google Scholar). Integration of data on individual receptors into organ system biology is providing a strategic focus for the field as it necessarily diversifies into more organ-specific topic areas. Major systems influenced by LPs include both the developing and adult cardiovascular system (12Osborne N. Stainier D.Y. Annu. Rev. Physiol. 2003; 65: 23-43Crossref PubMed Scopus (35) Google Scholar, 13Spiegel S. Milstien S. Nat. Rev. Mol. Cell. Biol. 2003; 4: 397-407Crossref PubMed Scopus (1791) Google Scholar, 50Yang A.H. Ishii I. Chun J. Biochim. Biophys. Acta. 2002; 1582: 197-203Crossref PubMed Scopus (81) Google Scholar), reproductive system (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar, 35Ishii I. Ye X. Friedman B. Kawamura S. Contos J.J. Kingsbury M.A. Yang A.H. Zhang G. Brown J.H. Chun J. J. Biol. Chem. 2002; 277: 25152-25159Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 51Tilly J.L. Kolesnick R.N. Biochim. Biophys. Acta. 2002; 1585: 135-138Crossref PubMed Scopus (83) Google Scholar), immune system (52Lee H. Liao J.J. Graeler M. Huang M.C. Goetzl E.J. Biochim. Biophys. Acta. 2002; 1582: 175-177Crossref PubMed Scopus (52) Google Scholar, 53Graler M.H. Goetzl E.J. Biochim. Biophys. Acta. 2002; 1582: 168-174Crossref PubMed Scopus (159) Google Scholar, 54Huang M.C. Graeler M. Shankar G. Spencer J. Goetzl E.J. Biochim. Biophys. Acta. 2002; 1582: 161-167Crossref PubMed Scopus (62) Google Scholar, 55Rosen H. Sanna G. Alfonso C. Immunol. Rev. 2003; 195: 160-177Crossref PubMed Scopus (93) Google Scholar, 56Brinkmann V. Lynch K.R. Curr. Opin. Immunol. 2002; 14: 569-575Crossref PubMed Scopus (254) Google Scholar), and nervous system (Fig. 3) (5Ishii I. Fukushima N. Ye X. Chun J. Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (663) Google Scholar, 8Fukushima N. Ishii I. Contos J.J. Weiner J.A. Chun J. Annu. Rev. Pharmacol. Toxicol. 2001; 41: 507-534Crossref PubMed Scopus (328) Google Scholar, 50Yang A.H. Ishii I. Chun J. Biochim. Biophys. Acta. 2002; 1582: 197-203Crossref PubMed Scopus (81) Google Scholar, 57Chun J. Weiner J.A. Fukushima N. Contos J.J. Zhang G. Kimura Y. Dubin A. Ishii I. Hecht J.H. Akita C. Kaushal D. Ann. N. Y. Acad. Sci. 2000; 905: 110-117Crossref PubMed Scopus (44) Google Scholar, 58Ye X. Fukushima N. Kingsbury M.A. Chun J. Neuroreport. 2002; 13: 2169-2175Crossref PubMed Scopus (62) Google Scholar, 59Fukushima N. Ye X. Chun J. Neuroscientist. 2002; 8: 540-550Crossref PubMed Scopus (23) Google Scholar); these represent only a partial list of influences considering the widespread expression of LP receptors viewed as a whole. Both LPA and S1P have been implicated in these influences, and the range of effects continues to increase. In addition to normal physiological processes, LP signaling has also been implicated in cancer (3Mills G.B. Moolenaar W.H. Nat. Rev. Cancer. 2003; 3: 582-591Crossref PubMed Scopus (963) Google Scholar, 60Mills G.B. Fang X. Lu Y. Hasegawa Y. Eder A. Tanyi J. Tabassam F.H. Mao M. Wang H. Cheng K.W. Nakayama Y. Kuo W. Erickson J. Gershenson D. Kohn E.C. Jaffe R. Bast Jr., R.C. Gray J. Gynecol. Oncol. 2003; 88: S88-S93Abstract Full Text PDF PubMed Scopus (19) Google Scholar), wound healing (16Yatomi Y. Ozaki Y. Ohmori T. Igarashi Y. Prostaglandins. 2001; 64: 107-122Crossref PubMed Scopus (168) Google Scholar), and atherosclerosis (39Siess W. Biochim. Biophys. Acta. 2002; 1582: 204-215Crossref PubMed Scopus (148) Google Scholar, 48Karliner J.S. Biochim. Biophys. Acta. 2002; 1582: 216-221Crossref PubMed Scopus (79) Google Scholar). Joining the effects of LPA and S1P, it is certain that other chemical forms of LPs and their cognate GPCRs will also complement the many studies noted here. Elucidating both physiological and pathophysiological roles mediated by LP GPCRs will undoubtedly fuel continued growth of this exciting field.
Referência(s)