A Review of the Role of Sphingosine-1-Phosphate in the Brain: An Important Mediator Implicated in the Central Nervous System



Sphingosine-1-phosphate (S1P) is a bioactive lipid that signals through a family of G protein-coupled receptors, consisting of 5 members, termed S1P1, S1P2, S1P3, S1P4 and S1P5. Activation of S1P results in the regulation of several cellular functions, including cell proliferation, process retraction, cell survival and migration. Deregulation of S1P receptor expression and/or the S1P signaling pathway may play an important role in the development in the treatment of neurological disorders. The aim of the present review is to summarize the S1P signaling pathway and S1P receptor expression in the cellular components of human and rodent brains. The published information will be helpful to delineate the important mechanisms in the development of neurological disorders such as Alzheimer’s disease, multiple sclerosis, and traumatic brain injury, and serve as a guideline for the designing of further studies investigating S1P involvement in the brain.



Sphingosine-1-phosphate, brain, neurons, glial cells, brain endothelial cells

Full Text:



T Hla. Physiological and pathological actions of sphingosine 1-phosphate. Semin. Cell Dev. Biol. 2004; 15, 513-20.

S Spiegel and S Milstien. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat. Rev. Mol. Cell Biol. 2003; 4, 397-407.

T Baumruker, F Bornancin and A Billich. The role of sphingosine and ceramide kinases in inflammatory responses. Immunol. Lett. 2005; 96, 175-85.

JD Saba and T Hla. Point-counterpoint of sphingosine 1-phosphate metabolism. Circ. Res. 2004; 94, 724-34.

L Bryan, BS Paugh, D Kapitonov, KM Wilczynska, SM Alvarez, SK Singh, S Milstien, S Spiegel and T Kordula. Sphingosine-1-phosphate and interleukin-1 independently regulate plasminogen activator inhibitor-1 and urokinase-type plasminogen activator receptor expression in glioblastoma cells: implications for invasiveness. Mol. Cancer Res. 2008; 6, 1469-77.

L Colombaioni and M Garcia-Gil. Sphingolipid metabolites in neural signalling and function. Brain Res. Brain Res. Rev. 2004; 46, 328-55.

A Olivera and S Spiegel. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 1993; 365, 557-60.

D English, Z Welch, AT Kovala, K Harvey, OV Volpert, DN Brindley and JG Garcia. Sphingosine 1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis. FASEB J. 2000; 14, 2255-65.

T Sano, D Baker, T Virag, A Wada, Y Yatomi, T Kobayashi, Y Igarashi and G Tigyi. Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine 1-phosphate generation in blood. J. Biol. Chem. 2002; 277, 21197-206.

P Hanel, P Andreani and MH Graler. Erythrocytes store and release sphingosine 1-phosphate in blood. FASEB J. 2007; 21, 1202-9.

R Pappu, SR Schwab, I Cornelissen, JP Pereira, JB Regard, Y Xu, E Camerer, YW Zheng, Y Huang, JG Cyster and SR Coughlin. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 2007; 316, 295-8.

E Malchinkhuu, K Sato, T Muraki, K Ishikawa, A Kuwabara and F Okajima. Assessment of the role of sphingosine 1-phosphate and its receptors in high-density lipoprotein-induced stimulation of astroglial cell function. Biochem. J. 2003; 370, 817-27.

F Mullershausen, LM Craveiro, Y Shin, M Cortes-Cros, F Bassilana, M Osinde, WL Wishart, D Guerini, M Thallmair, ME Schwab, R Sivasankaran, K Seuwen and KK Dev. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J. Neurochem. 2007; 102, 1151-61.

K Yamagata, M Tagami, Y Torii, F Takenaga, S Tsumagari, S Itoh, Y Yamori and Y Nara. Sphingosine 1-phosphate induces the production of glial cell line-derived neurotrophic factor and cellular proliferation in astrocytes. Glia 2003; 41, 199-206.

C Jaillard, S Harrison, B Stankoff, MS Aigrot, AR Calver, G Duddy, FS Walsh, MN Pangalos, N Arimura, K Kaibuchi, B Zalc and C Lubetzki. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J. Neurosci. 2005; 25, 1459-69.

HS Saini, RP Coelho, SK Goparaju, PS Jolly, M Maceyka, S Spiegel and C Sato-Bigbee. Novel role of sphingosine kinase 1 as a mediator of neurotrophin-3 action in oligodendrocyte progenitors. J. Neurochem. 2005; 95, 1298-310.

AJ MacLennan, PR Carney, WJ Zhu, AH Chaves, J Garcia, JR Grimes, KJ Anderson, SN Roper and N Lee. An essential role for the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate receptor in neuronal excitability. Eur. J. Neurosci. 2001; 14, 203-9.

LC Edsall and S Spiegel. Enzymatic measurement of sphingosine 1-phosphate. Anal. Biochem. 1999; 272, 80-6.

KK Dev, F Mullershausen, H Mattes, RR Kuhn, G Bilbe, D Hoyer and Mir A. Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol. Ther. 2008; 117, 77-93.

N Yu, KD Lariosa-Willingham, FF Lin, M Webb and TS Rao. Characterization of lysophosphatidic acid and sphingosine-1-phosphate-mediated signal transduction in rat cortical oligodendrocytes. Glia 2004; 45, 17-27.

DS Im, CE Heise, N Ancellin, BF O'Dowd, GJ Shei, RP Heavens, MR Rigby, T Hla, S Mandala, G McAllister, SR George and KR Lynch. Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J. Biol. Chem. 2000; 275, 14281-6.

H Nishimura, T Akiyama, I Irei, S Hamazaki and Y Sadahira. Cellular localization of sphingosine-1-phosphate receptor 1 expression in the human central nervous system. J. Histochem. Cytochem. 2010; 58, 847-56.

N Blondeau, Y Lai, S Tyndall, M Popolo, K Topalkara, JK Pru, L Zhang, H Kim, JK Liao, K Ding and C Waeber. Distribution of sphingosine kinase activity and mRNA in rodent brain. J. Neurochem. 2007; 103, 509-17.

SG Payne, S Milstien and S Spiegel. Sphingosine-1-phosphate: dual messenger functions. FEBS Lett. 2002; 531, 54-7.

J Harada, M Foley, MA Moskowitz and C Waeber. Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J. Neurochem. 2004; 88, 1026-39.

CS Tham, FF Lin, TS Rao, N Yu, M Webb. Microglial activation state and lysophospholipid acid receptor expression. Int. J. Dev. Neurosci. 2003; 21, 431-43.

SS Chae, RL Proia and T Hla. Constitutive expression of the S1P1 receptor in adult tissues. Prostag. Other Lipid Mediat. 2004; 73, 141-50.

K Terai, T Soga, M Takahashi, M Kamohara, K Ohno, S Yatsugi, M Okada and T Yamaguchi. Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS. Neuroscience 2003; 116, 1053-62.

CG Jung, HJ Kim, VE Miron, S Cook, TE Kennedy, CA Foster, JP Antel and B Soliven. Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia 2007; 55, 1656-67.

AS Novgorodov, M El-Alwani, J Bielawski, LM Obeid and TI Gudz. Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J. 2007; 21, 1503-14.

TS Rao, KD Lariosa-Willingham, FF Lin, EL Palfreyman, N Yu, J Chun and M Webb. Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. Brain Res. 2003; 990, 182-94.

M Pekny and M Nilsson. Astrocyte activation and reactive gliosis. Glia 2005; 50, 427-34.

NJ Abbott. Astrocyte-endothelial interactions and blood-brain barrier permeability. J. Anat. 2002; 200, 629-38.

SE Alvarez, S Milstien and S Spiegel. Autocrine and paracrine roles of sphingosine-1-phosphate. Trends Endocrinol. Metab. 2007; 18, 300-7.

I Fischer, C Alliod, N Martinier, J Newcombe, C Brana and S Pouly. Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PLoS One. 2011; 6, e23905.

R Bassi, V Anelli, P Giussani, G Tettamanti, P Viani and L Riboni. Sphingosine-1-phosphate is released by cerebellar astrocytes in response to bFGF and induces astrocyte proliferation through Gi-protein-coupled receptors. Glia 2006; 53, 621-30.

A Pebay, M Toutant, J Premont, CF Calvo, L Venance, J Cordier, J Glowinski and M Tencé. Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades. Eur. J. Neurosci. 2001; 13, 2067-76.

SD Sorensen, O Nicole, RD Peavy, LM Montoya, CJ Lee, TJ Murphy, SF Traynelis and JR Hepler. Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol. Pharmacol. 2003; 64, 1199-209.

ST Dheen, C Kaur and EA Ling. Microglial activation and its implications in the brain diseases. Curr. Med. Chem. 2007; 14, 1189-97.

D Nayak, Y Huo, WX Kwang, PN Pushparaj, SD Kumar, EA Ling and ST Dheen. Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. Neuroscience 2010; 166, 132-44.

LW Maines, LR Fitzpatrick, KJ French, Y Zhuang, Z Xia, SN Keller, JJ Upson and CD Smith. Suppression of ulcerative colitis in mice by orally available inhibitors of sphingosine kinase. Dig. Dis. Sci. 2008; 53, 997-1012.

V Brinkmann. FTY720: mechanism of action and potential benefit in organ transplantation. Yonsei. Med. J. 2004; 45, 991-7.

JF Lee, Q Zeng, H Ozaki, L Wang, AR Hand, T Hla, E Wang and MJ Lee. Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity. J. Biol. Chem. 2006; 281, 29190-200.

JF Lee, H Ozaki, X Zhan, E Wang, T Hla and MJ Lee. Sphingosine-1-phosphate signaling regulates lamellipodia localization of cortactin complexes in endothelial cells. Histochem. Cell Biol. 2006; 126, 297-304.

A Pilorget, M Demeule, S Barakat, J Marvaldi, J Luis and R Beliveau. Modulation of P-glycoprotein function by sphingosine kinase-1 in brain endothelial cells. J. Neurochem. 2007; 100, 1203-10.

C Waeber, N Blondeau and S Salomone. Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors. Drug News Perspect. 2004; 17, 365-82.


  • There are currently no refbacks.


Online ISSN: 2228-835X


Last updated: 20 June 2019