Lysophospholipid (S1P) receptors
More information on this family may be found on the IUPHAR-DB family and introduction pages.
Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Lysophospholipid receptors; [5]) are activated by the endogenous lipid derivatives sphingosine 1-phosphate (S1P) and sphingosyl phosphorylcholine (SPC). Originally identified as members of the endothelial differentiation gene (edg) family along with lysophosphatidic acid receptors, the gene names have recently been updated to S1PR1, etc. to reflect the receptor function of these proteins. S1P has also been described to act at intracellular sites [15], although most cellular phenomena ascribed to S1P can be explained by receptor-mediated mechanisms. The relationship between recombinant and endogenously expressed receptors is unclear. Radioligand binding has been conducted in heterologous expression systems using [32P]S1P (e.g [10]). In native systems, analysis of binding data is complicated by metabolism and high levels of nonspecific binding. Targeted deletion of several S1P receptors and key enzymes involved in S1P biosynthesis or degradation has clarified signalling pathways and physiological roles.
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Receptors 
|
|||||||||||||||||||||
|
|||||||||||||||||||||
|
|||||||||||||||||||||
|
|||||||||||||||||||||
|
Aktas, O; Küry, P; Kieseier, B; Hartung, HP. (2010) Fingolimod is a potential novel therapy for multiple sclerosis. Nat Rev Neurol, 6 (7): 373-82. [PMID:20551946]
Bartke, N; Hannun, YA. (2009) Bioactive sphingolipids: metabolism and function. J. Lipid Res., 50 Suppl: S91-6. [PMID:19017611]
Chi, H. (2011) Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol. Sci., 32 (1): 16-24. [PMID:21159389]
Choi, JW; Gardell, SE; Herr, DR; Rivera, R; Lee, CW; Noguchi, K; Teo, ST; Yung, YC; Lu, M; Kennedy, G; et al.. (2011) 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., 108 (2): 751-6. [PMID:21177428]
Choi, JW; Lee, CW; Chun, J. (2008) Biological roles of lysophospholipid receptors revealed by genetic null mice: an update. Biochim. Biophys. Acta, 1781 (9): 531-9. [PMID:18407842]
Chun, J; Hla, T; Lynch, KR; Spiegel, S; Moolenaar, WH. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol. Rev., 62 (4): 579-87. [PMID:21079037]
Cohen, JA; Chun, J. (2011) Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann. Neurol., 69 (5): 759-77. [PMID:21520239]
Hla, T; Brinkmann, V. (2011) Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation. Neurology, 76 (8 Suppl 3): S3-8. [PMID:21339489]
Hla, T; Venkataraman, K; Michaud, J. (2008) The vascular S1P gradient-cellular sources and biological significance. Biochim. Biophys. Acta, 1781 (9): 477-82. [PMID:18674637]
Huwiler, A; Pfeilschifter, J. (2009) Lipids as targets for novel anti-inflammatory therapies. Pharmacol. Ther., 124 (1): 96-112. [PMID:19576246]
Igarashi, J; Michel, T. (2009) Sphingosine-1-phosphate and modulation of vascular tone. Cardiovasc. Res., 82 (2): 212-20. [PMID:19233865]
Ishii, S; Noguchi, K; Yanagida, K. (2009) Non-Edg family lysophosphatidic acid (LPA) receptors. Prostaglandins Other Lipid Mediat., 89 (3-4): 57-65. [PMID:19524700]
Kim, RH; Takabe, K; Milstien, S; Spiegel, S. (2009) Export and functions of sphingosine-1-phosphate. Biochim. Biophys. Acta, 1791 (7): 692-6. [PMID:19268560]
Levkau, B. (2008) Sphingosine-1-phosphate in the regulation of vascular tone: a finely tuned integration system of S1P sources, receptors, and vascular responsiveness. Circ. Res., 103 (3): 231-3. [PMID:18669929]
Marsolais, D; Rosen, H. (2009) Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat Rev Drug Discov, 8 (4): 297-307. [PMID:19300460]
Means, CK; Brown, JH. (2009) Sphingosine-1-phosphate receptor signalling in the heart. Cardiovasc. Res., 82 (2): 193-200. [PMID:19282351]
Meyer zu Heringdorf, D; Jakobs, KH. (2007) Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim. Biophys. Acta, 1768 (4): 923-40. [PMID:17078925]
Milstien, S; Gude, D; Spiegel, S. (2007) Sphingosine 1-phosphate in neural signalling and function. Acta Paediatr Suppl, 96 (455): 40-3. [PMID:17391440]
Nixon, GF. (2009) Sphingolipids in inflammation: pathological implications and potential therapeutic targets. Br. J. Pharmacol., 158 (4): 982-93. [PMID:19563535]
Pappu, R; Schwab, SR; Cornelissen, I; Pereira, JP; Regard, JB; Xu, Y; Camerer, E; Zheng, YW; Huang, Y; Cyster, JG; et al.. (2007) Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science, 316 (5822): 295-8. [PMID:17363629]
Pyne, NJ; Long, JS; Lee, SC; Loveridge, C; Gillies, L; Pyne, S. (2009) New aspects of sphingosine 1-phosphate signaling in mammalian cells. Adv. Enzyme Regul., 49 (1): 214-21. [PMID:19534035]
Pyne, NJ; Pyne, S. (2010) Sphingosine 1-phosphate and cancer. Nat. Rev. Cancer, 10 (7): 489-503. [PMID:20555359]
Pyne, S; Pyne, NJ. (2011) Translational aspects of sphingosine 1-phosphate biology. Trends Mol Med, 17 (8): 463-72. [PMID:21514226]
Rosen, H; Gonzalez-Cabrera, P; Marsolais, D; Cahalan, S; Don, AS; Sanna, MG. (2008) Modulating tone: the overture of S1P receptor immunotherapeutics. Immunol. Rev., 223: 221-35. [PMID:18613839]
Rosen, H; Gonzalez-Cabrera, PJ; Sanna, MG; Brown, S. (2009) Sphingosine 1-phosphate receptor signaling. Annu. Rev. Biochem., 78: 743-68. [PMID:19231986]
Shimizu, T. (2009) Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu. Rev. Pharmacol. Toxicol., 49: 123-50. [PMID:18834304]
Spiegel, S; Milstien, S. (2011) The outs and the ins of sphingosine-1-phosphate in immunity. Nat. Rev. Immunol., 11 (6): 403-15. [PMID:21546914]
Takabe, K; Paugh, SW; Milstien, S; Spiegel, S. (2008) "Inside-out" signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol. Rev., 60 (2): 181-95. [PMID:18552276]
1. Albert, R; Hinterding, K; Brinkmann, V; Guerini, D; Müller-Hartwieg, C; Knecht, H; Simeon, C; Streiff, M; Wagner, T; Welzenbach, K; et al.. (2005) Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer. J. Med. Chem., 48 (16): 5373-7. [PMID:16078855]
2. Ancellin, N; Hla, T. (1999) Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5. J. Biol. Chem., 274 (27): 18997-9002. [PMID:10383399]
3. Brinkmann, V; Davis, MD; Heise, CE; Albert, R; Cottens, S; Hof, R; Bruns, C; Prieschl, E; Baumruker, T; Hiestand, P; et al.. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem., 277 (24): 21453-7. [PMID:11967257]
4. Choi, JW; Gardell, SE; Herr, DR; Rivera, R; Lee, CW; Noguchi, K; Teo, ST; Yung, YC; Lu, M; Kennedy, G; et al.. (2011) 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., 108 (2): 751-6. [PMID:21177428]
5. Chun, J; Hla, T; Lynch, KR; Spiegel, S; Moolenaar, WH. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol. Rev., 62 (4): 579-87. [PMID:21079037]
6. Cohen, JA; Chun, J. (2011) Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann. Neurol., 69 (5): 759-77. [PMID:21520239]
7. Im, DS; Heise, CE; Ancellin, N; O'Dowd, BF; Shei, GJ; Heavens, RP; Rigby, MR; Hla, T; Mandala, S; McAllister, G; et al.. (2000) Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J. Biol. Chem., 275 (19): 14281-6. [PMID:10799507]
8. Mandala, S; Hajdu, R; Bergstrom, J; Quackenbush, E; Xie, J; Milligan, J; Thornton, R; Shei, GJ; Card, D; Keohane, C; et al.. (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science, 296 (5566): 346-9. [PMID:11923495]
9. Marsolais, D; Rosen, H. (2009) Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat Rev Drug Discov, 8 (4): 297-307. [PMID:19300460]
10. Okamoto, H; Takuwa, N; Gonda, K; Okazaki, H; Chang, K; Yatomi, Y; Shigematsu, H; Takuwa, Y. (1998) EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. J. Biol. Chem., 273 (42): 27104-10. [PMID:9765227]
11. Osada, M; Yatomi, Y; Ohmori, T; Ikeda, H; Ozaki, Y. (2002) Enhancement of sphingosine 1-phosphate-induced migration of vascular endothelial cells and smooth muscle cells by an EDG-5 antagonist. Biochem. Biophys. Res. Commun., 299 (3): 483-7. [PMID:12445827]
12. Pan, S; Mi, Y; Pally, C; Beerli, C; Chen, A; Guerini, D; Hinterding, K; Nuesslein-Hildesheim, B; Tuntland, T; Lefebvre, S; et al.. (2006) A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem. Biol., 13 (11): 1227-34. [PMID:17114004]
13. Rosen, H; Gonzalez-Cabrera, PJ; Sanna, MG; Brown, S. (2009) Sphingosine 1-phosphate receptor signaling. Annu. Rev. Biochem., 78: 743-68. [PMID:19231986]
14. Sanna, MG; Wang, SK; Gonzalez-Cabrera, PJ; Don, A; Marsolais, D; Matheu, MP; Wei, SH; Parker, I; Jo, E; Cheng, WC; et al.. (2006) Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat. Chem. Biol., 2 (8): 434-41. [PMID:16829954]
15. Takabe, K; Paugh, SW; Milstien, S; Spiegel, S. (2008) "Inside-out" signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol. Rev., 60 (2): 181-95. [PMID:18552276]
16. Van Brocklyn, JR; Gräler, MH; Bernhardt, G; Hobson, JP; Lipp, M; Spiegel, S. (2000) Sphingosine-1-phosphate is a ligand for the G protein-coupled receptor EDG-6. Blood, 95 (8): 2624-9. [PMID:10753843]
|
 @GuidetoPHARM  Like us on Facebook Privacy and Cookie Policy |
The immunomodulator fingolimod (FTY720) may be phosphorylated in vivo [1] to generate a relatively potent agonist with activity at S1P1, S1P3, S1P4 and S1P5 receptors [3,8]. VPC23019 and VPC44116 have antagonist activity at S1P1 and S1P3 receptors [9]. This compound has received world-wide approval as the first oral therapy for relapsing forms of Multiple Sclerosis, with a novel mechanism of action [4,6].