Sphingosine 1-phosphate receptor 3 and RhoA signaling mediate inflammatory gene expression in astrocytes.
Authors:
Journal: Journal of neuroinflammation
Publication Type: Journal Article
Date: 2017
DOI: PMC5455202
ID: 28577576
Abstract
Sphingosine 1-phosphate (S1P) signals through G protein-coupled receptors to elicit a wide range of cellular responses. In CNS injury and disease, the blood-brain barrier is compromised, causing leakage of S1P from blood into the brain. S1P can also be locally generated through the enzyme sphingosine kinase-1 (Sphk1). Our previous studies demonstrated that S1P activates inflammation in murine astrocytes. The S1P receptor subtype has been most associated with CNS disease, particularly multiple sclerosis. S1P is most highly expressed and upregulated on astrocytes, however, thus we explored the involvement of this receptor in inflammatory astrocytic responses.
Chemical List
- Cytokines|||RNA, Messenger|||RNA, Small Interfering|||Receptors, Lysosphingolipid|||Vascular Endothelial Growth Factor A|||Ptgs2 protein, mouse|||Cyclooxygenase 2|||rhoA GTP-Binding Protein
Reference List
- Camerer E, Regard JB, Cornelissen I, Srinivasan Y, Duong DN, Palmer D, Pham TH, Wong JS, Pappu R, Coughlin SR. Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J Clin Invest. 2009;119:1871–1879.|||Anelli V, Bassi R, Tettamanti G, Viani P, Riboni L. Extracellular release of newly synthesized sphingosine-1-phosphate by cerebellar granule cells and astrocytes. J Neurochem. 2005;92:1204–1215. doi: 10.1111/j.1471-4159.2004.02955.x.|||Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG, Coughlin SR. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science. 2007;316:295–298. doi: 10.1126/science.1139221.|||Yatomi Y, Ohmori T, Rile G, Kazama F, Okamoto H, Sano T, Satoh K, Kume S, Tigyi G, Igarashi Y, Ozaki Y. Sphingosine 1-phosphate as a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells. Blood. 2000;96:3431–3438.|||Yatomi Y, Igarashi Y, Yang L, Hisano N, Qi R, Asazuma N, Satoh K, Ozaki Y, Kume S. Sphingosine 1-phosphate, a bioactive sphingolipid abundantly stored in platelets, is a normal constituent of human plasma and serum. J Biochem. 1997;121:969–973. doi: 10.1093/oxfordjournals.jbchem.a021681.|||Ishii I, Fukushima N, Ye X, Chun J. Lysophospholipid receptors: signaling and biology. Annu Rev Biochem. 2004;73:321–354. doi: 10.1146/annurev.biochem.73.011303.073731.|||Kihara Y, Maceyka M, Spiegel S, Chun J. Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br J Pharmacol. 2014;171:3575–3594. doi: 10.1111/bph.12678.|||Rao TS, Lariosa-Willingham KD, Lin FF, Palfreyman EL, Yu N, Chun J, Webb M. Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. Brain Res. 2003;990:182–194. doi: 10.1016/S0006-8993(03)03527-3.|||Tham CS, Lin FF, Rao TS, Yu N, Webb M. Microglial activation state and lysophospholipid acid receptor expression. Int J Dev Neurosci. 2003;21:431–443. doi: 10.1016/j.ijdevneu.2003.09.003.|||Toman RE, Payne SG, Watterson KR, Maceyka M, Lee NH, Milstien S, Bigbee JW, Spiegel S. Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension. J Cell Biol. 2004;166:381–392. doi: 10.1083/jcb.200402016.|||Yu N, Lariosa-Willingham KD, Lin FF, Webb M, Rao TS. Characterization of lysophosphatidic acid and sphingosine-1-phosphate-mediated signal transduction in rat cortical oligodendrocytes. Glia. 2004;45:17–27. doi: 10.1002/glia.10297.|||Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929–11947. doi: 10.1523/JNEUROSCI.1860-14.2014.|||Choi JW, Chun J. Lysophospholipids and their receptors in the central nervous system. Biochim Biophys Acta. 2013;1:20–32.|||Hamby ME, Sofroniew MV. Reactive astrocytes as therapeutic targets for CNS disorders. Neurotherapeutics. 2010;7:494–506. doi: 10.1016/j.nurt.2010.07.003.|||Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 1997;20:570–577. doi: 10.1016/S0166-2236(97)01139-9.|||Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 2009;32:638–647. doi: 10.1016/j.tins.2009.08.002.|||Sofroniew MV. Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist. 2014;20:160–172. doi: 10.1177/1073858413504466.|||Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35. doi: 10.1007/s00401-009-0619-8.|||Miljkovic D, Timotijevic G, Mostarica Stojkovic M. Astrocytes in the tempest of multiple sclerosis. FEBS Lett. 2011;585:3781–3788. doi: 10.1016/j.febslet.2011.03.047.|||Williams A, Piaton G, Lubetzki C. Astrocytes—friends or foes in multiple sclerosis? Glia. 2007;55:1300–1312. doi: 10.1002/glia.20546.|||Sorensen SD, Nicole O, Peavy RD, Montoya LM, Lee CJ, Murphy TJ, Traynelis SF, Hepler JR. Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol Pharmacol. 2003;64:1199–1209. doi: 10.1124/mol.64.5.1199.|||Pebay A, Toutant M, Premont J, Calvo CF, Venance L, Cordier J, Glowinski J, Tence M. Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades. Eur J Neurosci. 2001;13:2067–2076. doi: 10.1046/j.0953-816x.2001.01585.x.|||Moon E, Han JE, Jeon S, Ryu JH, Choi JW, Chun J. Exogenous S1P exposure potentiates ischemic stroke damage that is reduced possibly by inhibiting S1P receptor signaling. Mediators Inflamm. 2015;2015:492659. doi: 10.1155/2015/492659.|||Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–415. doi: 10.1056/NEJMoa0907839.|||Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401. doi: 10.1056/NEJMoa0909494.|||Cohen JA, Chun J. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69:759–777. doi: 10.1002/ana.22426.|||Kihara Y, Mizuno H, Chun J. Lysophospholipid receptors in drug discovery. Exp Cell Res. 2015;333:171–177. doi: 10.1016/j.yexcr.2014.11.020.|||Brinkmann V, Lynch KR. FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr Opin Immunol. 2002;14:569–575. doi: 10.1016/S0952-7915(02)00374-6.|||Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296:346–349. doi: 10.1126/science.1070238.|||Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW, Noguchi K, Teo ST, Yung YC, Lu M, Kennedy G, Chun J. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A. 2011;108:751–756. doi: 10.1073/pnas.1014154108.|||Mullershausen F, Craveiro LM, Shin Y, Cortes-Cros M, Bassilana F, Osinde M, Wishart WL, Guerini D, Thallmair M, Schwab ME, Sivasankaran R, Seuwen K, Dev KK. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem. 2007;102:1151–1161. doi: 10.1111/j.1471-4159.2007.04629.x.|||Hamby ME, Coppola G, Ao Y, Geschwind DH, Khakh BS, Sofroniew MV. Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G-protein-coupled receptors. J Neurosci. 2012;32:14489–14510. doi: 10.1523/JNEUROSCI.1256-12.2012.|||Van Doorn R, Van Horssen J, Verzijl D, Witte M, Ronken E, Van Het Hof B, Lakeman K, Dijkstra CD, Van Der Valk P, Reijerkerk A, Alewijnse AE, Peters SL, De Vries HE. Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia. 2010;58:1465–1476.|||Fischer I, Alliod C, Martinier N, Newcombe J, Brana C, Pouly S. Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PLoS One. 2011;6:e23905. doi: 10.1371/journal.pone.0023905.|||Wu YP, Mizugishi K, Bektas M, Sandhoff R, Proia RL. Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease. Hum Mol Genet. 2008;17:2257–2264. doi: 10.1093/hmg/ddn126.|||Ishii I, Ye X, Friedman B, Kawamura S, Contos JJ, Kingsbury MA, Yang AH, Zhang G, Brown JH, Chun J. Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (S1P) receptors, S1P(2)/LP(B2)/EDG-5 and S1P(3)/LP(B3)/EDG-3. J Biol Chem. 2002;277:25152–25159. doi: 10.1074/jbc.M200137200.|||Siehler S, Manning DR. Pathways of transduction engaged by sphingosine 1-phosphate through G protein-coupled receptors. Biochim Biophys Acta. 2002;1582:94–99. doi: 10.1016/S1388-1981(02)00142-7.|||Mutoh T, Rivera R, Chun J. Insights into the pharmacological relevance of lysophospholipid receptors. Br J Pharmacol. 2012;165:829–844. doi: 10.1111/j.1476-5381.2011.01622.x.|||Dusaban SS, Kunkel MT, Smrcka AV, Brown JH. Thrombin promotes sustained signaling and inflammatory gene expression through the CDC25 and Ras-associating domains of phospholipase C-epsilon. J Biol Chem. 2015;44:26776–83.|||Dusaban SS, Purcell NH, Rockenstein E, Masliah E, Cho MK, Smrcka AV, Brown JH. Phospholipase C epsilon links G protein-coupled receptor activation to inflammatory astrocytic responses. Proc Natl Acad Sci U S A. 2013;110:3609–3614. doi: 10.1073/pnas.1217355110.|||Post GR, Collins LR, Kennedy ED, Moskowitz SA, Aragay AM, Goldstein D, Brown JH. Coupling of the thrombin receptor to G12 may account for selective effects of thrombin on gene expression and DNA synthesis in 1321N1 astrocytoma cells. Mol Biol Cell. 1996;7:1679–1690. doi: 10.1091/mbc.7.11.1679.|||Walsh CT, Radeff-Huang J, Matteo R, Hsiao A, Subramaniam S, Stupack D, Brown JH. Thrombin receptor and RhoA mediate cell proliferation through integrins and cysteine-rich protein 61. FASEB J. 2008;22:4011–4021. doi: 10.1096/fj.08-113266.|||Yu OM, Miyamoto S, Brown JH. Myocardin-related transcription factor a and yes-associated protein exert dual control in G protein-coupled receptor- and RhoA-mediated transcriptional regulation and cell proliferation. Mol Cell Biol. 2015;36:39–49.|||Citro S, Malik S, Oestreich EA, Radeff-Huang J, Kelley GG, Smrcka AV, Brown JH. Phospholipase Cepsilon is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation. Proc Natl Acad Sci U S A. 2007;104:15543–15548. doi: 10.1073/pnas.0702943104.|||Sanna MG, Vincent KP, Repetto E, Nguyen N, Brown SJ, Abgaryan L, Riley SW, Leaf NB, Cahalan SM, Kiosses WB, Kohno Y, Brown JH, McCulloch AD, Rosen H, Gonzalez-Cabrera PJ. Bitopic sphingosine 1-phosphate receptor 3 (S1P3) antagonist rescue from complete heart block: pharmacological and genetic evidence for direct S1P3 regulation of mouse cardiac conduction. Mol Pharmacol. 2016;89:176–186. doi: 10.1124/mol.115.100222.|||Ishii I, Friedman B, Ye X, Kawamura S, McGiffert C, Contos JJ, Kingsbury MA, Zhang G, Brown JH, Chun J. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3. J Biol Chem. 2001;276:33697–33704. doi: 10.1074/jbc.M104441200.|||Pan H, Wang H, Wang X, Zhu L, Mao L. The absence of Nrf2 enhances NF-kappaB-dependent inflammation following scratch injury in mouse primary cultured astrocytes. Mediators Inflamm. 2012;2012:217580. doi: 10.1155/2012/217580.|||Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3:1101–1108. doi: 10.1038/nprot.2008.73.|||Means CK, Xiao CY, Li Z, Zhang T, Omens JH, Ishii I, Chun J, Brown JH. Sphingosine 1-phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2007;292:H2944–H2951. doi: 10.1152/ajpheart.01331.2006.|||Jo E, Bhhatarai B, Repetto E, Guerrero M, Riley S, Brown SJ, Kohno Y, Roberts E, Schurer SC, Rosen H. Novel selective allosteric and bitopic ligands for the S1P(3) receptor. ACS Chem Biol. 2012;7:1975–1983. doi: 10.1021/cb300392z.|||Guerrero M, Poddutoori R, Urbano M, Peng X, Spicer TP, Chase PS, Hodder PS, Schaeffer MT, Brown S, Rosen H, Roberts E. Discovery, design and synthesis of a selective S1P(3) receptor allosteric agonist. Bioorg Med Chem Lett. 2013;23:6346–6349. doi: 10.1016/j.bmcl.2013.09.075.|||Cen B, Selvaraj A, Burgess RC, Hitzler JK, Ma Z, Morris SW, Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes. Mol Cell Biol. 2003;23:6597–6608. doi: 10.1128/MCB.23.18.6597-6608.2003.|||Miralles F, Posern G, Zaromytidou AI, Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell. 2003;113:329–342. doi: 10.1016/S0092-8674(03)00278-2.|||Kohama T, Olivera A, Edsall L, Nagiec MM, Dickson R, Spiegel S. Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem. 1998;273:23722–23728. doi: 10.1074/jbc.273.37.23722.|||Ellwardt E, Zipp F. Molecular mechanisms linking neuroinflammation and neurodegeneration in MS. Exp Neurol. 2014;262 Pt A:8–17. doi: 10.1016/j.expneurol.2014.02.006.|||Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918–934. doi: 10.1016/j.cell.2010.02.016.|||Heneka MT, O'Banion MK, Terwel D, Kummer MP. Neuroinflammatory processes in Alzheimer's disease. J Neural Transm. 2010;117:919–947. doi: 10.1007/s00702-010-0438-z.|||Minghetti L. Role of COX-2 in inflammatory and degenerative brain diseases. Subcell Biochem. 2007;42:127–141. doi: 10.1007/1-4020-5688-5_5.|||Sofroniew MV. Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci. 2015;16:249–263. doi: 10.1038/nrn3898.|||Hoffmann FS, Hofereiter J, Rubsamen H, Melms J, Schwarz S, Faber H, Weber P, Putz B, Loleit V, Weber F, Hohlfeld R, Meinl E, Krumbholz M. Fingolimod induces neuroprotective factors in human astrocytes. J Neuroinflammation. 2015;12:184. doi: 10.1186/s12974-015-0393-6.|||Colombo E, Di Dario M, Capitolo E, Chaabane L, Newcombe J, Martino G, Farina C. Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol. 2014;76:325–337. doi: 10.1002/ana.24217.|||Burgos M, Fradejas N, Calvo S, Kang SU, Tranque P, Lubec G. A proteomic analysis of PKCepsilon targets in astrocytes: implications for astrogliosis. Amino Acids. 2011;40:641–651. doi: 10.1007/s00726-010-0691-3.|||Schachtrup C, Ryu JK, Helmrick MJ, Vagena E, Galanakis DK, Degen JL, Margolis RU, Akassoglou K. Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage. J Neurosci. 2010;30:5843–5854. doi: 10.1523/JNEUROSCI.0137-10.2010.|||Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, Mariani JN, Mahase S, Dutta DJ, Seto J, Kramer EG, Ferrara N, Sofroniew MV, John GR. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J Clin Invest. 2012;7:2454–68.|||Haseloff RF, Blasig IE, Bauer HC, Bauer H. In search of the astrocytic factor(s) modulating blood-brain barrier functions in brain capillary endothelial cells in vitro. Cell Mol Neurobiol. 2005;25:25–39. doi: 10.1007/s10571-004-1375-x.|||Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53. doi: 10.1038/nrn1824.|||Baeten KM, Akassoglou K. Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke. Dev Neurobiol. 2011;71:1018–1039. doi: 10.1002/dneu.20954.|||Garris CS, Wu L, Acharya S, Arac A, Blaho VA, Huang Y, Moon BS, Axtell RC, Ho PP, Steinberg GK, Lewis DB, Sobel RA, Han DK, Steinman L, Snyder MP, Hla T, Han MH. Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat Immunol. 2013;14:1166–1172. doi: 10.1038/ni.2730.|||Paugh BS, Bryan L, Paugh SW, Wilczynska KM, Alvarez SM, Singh SK, Kapitonov D, Rokita H, Wright S, Griswold-Prenner I, Milstien S, Spiegel S, Kordula T. Interleukin-1 regulates the expression of sphingosine kinase 1 in glioblastoma cells. J Biol Chem. 2009;284:3408–3417. doi: 10.1074/jbc.M807170200.|||Nayak D, Huo Y, Kwang WX, Pushparaj PN, Kumar SD, Ling EA, Dheen ST. Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. Neuroscience. 2010;166:132–144. doi: 10.1016/j.neuroscience.2009.12.020.|||Volzke A, Koch A, Meyer Zu Heringdorf D, Huwiler A, Pfeilschifter J. Sphingosine 1-phosphate (S1P) induces COX-2 expression and PGE2 formation via S1P receptor 2 in renal mesangial cells. Biochim Biophys Acta. 1841;2014:11–21.|||Sobel K, Monnier L, Menyhart K, Bolinger M, Studer R, Nayler O, Gatfield J. FTY720 phosphate activates sphingosine-1-phosphate receptor 2 and selectively couples to Galpha12/13/Rho/ROCK to induce myofibroblast contraction. Mol Pharmacol. 2015;87:916–927. doi: 10.1124/mol.114.097261.|||Skoura A, Sanchez T, Claffey K, Mandala SM, Proia RL, Hla T. Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina. J Clin Invest. 2007;117:2506–2516. doi: 10.1172/JCI31123.|||Bryan L, Kordula T, Spiegel S, Milstien S. Regulation and functions of sphingosine kinases in the brain. Biochim Biophys Acta. 2008;1781:459–466. doi: 10.1016/j.bbalip.2008.04.008.|||Groves A, Kihara Y, Chun J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci. 2013;328:9–18. doi: 10.1016/j.jns.2013.02.011.|||Forrest M, Sun SY, Hajdu R, Bergstrom J, Card D, Doherty G, Hale J, Keohane C, Meyers C, Milligan J, Mills S, Nomura N, Rosen H, Rosenbach M, Shei GJ, Singer II, Tian M, West S, White V, Xie J, Proia RL, Mandala S. Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J Pharmacol Exp Ther. 2004;309:758–768. doi: 10.1124/jpet.103.062828.|||Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9:883–897. doi: 10.1038/nrd3248.|||Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N, Rosen H. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem. 2004;279:13839–13848. doi: 10.1074/jbc.M311743200.|||Sensken SC, Staubert C, Keul P, Levkau B, Schoneberg T, Graler MH. Selective activation of G alpha i mediated signalling of S1P3 by FTY720-phosphate. Cell Signal. 2008;20:1125–1133. doi: 10.1016/j.cellsig.2008.01.019.|||Chun J, Brinkmann V. A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya) Discov Med. 2011;12:213–228.|||Nicole O, Goldshmidt A, Hamill CE, Sorensen SD, Sastre A, Lyuboslavsky P, Hepler JR, McKeon RJ, Traynelis SF. Activation of protease-activated receptor-1 triggers astrogliosis after brain injury. J Neurosci. 2005;25:4319–4329. doi: 10.1523/JNEUROSCI.5200-04.2005.|||Davalos D, Baeten KM, Whitney MA, Mullins ES, Friedman B, Olson ES, Ryu JK, Smirnoff DS, Petersen MA, Bedard C, Degen JL, Tsien RY, Akassoglou K. Early detection of thrombin activity in neuroinflammatory disease. Ann Neurol. 2014;75:303–308. doi: 10.1002/ana.24078.|||Kim HN, Kim YR, Ahn SM, Lee SK, Shin HK, Choi BT. Protease activated receptor-1 antagonist ameliorates the clinical symptoms of experimental autoimmune encephalomyelitis via inhibiting breakdown of blood-brain barrier. J Neurochem. 2015;135:577–588. doi: 10.1111/jnc.13285.