Sphingosine 1-phosphate enhances the excitability of rat sensory neurons through activation of sphingosine 1-phosphate receptors 1 and/or 3

Journal of Neuroinflammation

Grant D Nicol¹  Miguel Guerrero³  Joanne Kays¹  Jun-nan Li⁴  Chao Li² 

[1] Department of Pharmacology and Toxicology, School of Medicine, Indiana University, 635 Barnhill Drive, Indianapolis 46202, IN, USA;Medical Neuroscience Program, School of Medicine, Indiana University, Indianapolis 46202, IN, USA;Department of Chemistry, The Scripps Research Institute, La Jolla 92037, CA, USA;Department of Pharmacology, Harbin Medical University, Harbin, Peoples’ Republic of China

关键词: Dorsal root ganglia;    Sensory neuron;    Sphingosine 1-phosphate;    Sensitization;    Excitability;   

Others  :  1227096
DOI  :  10.1186/s12974-015-0286-8

 received in 2015-01-05, accepted in 2015-03-24,  发布年份 2015

【 摘 要 】

Background

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts through a family of five G-protein-coupled receptors (S1PR_1–5) and plays a key role in regulating the inflammatory response. Our previous studies demonstrated that rat sensory neurons express the mRNAs for all five S1PRs and that S1P increases neuronal excitability primarily, but not exclusively, through S1PR₁. This raises the question as to which other S1PRs mediate the enhanced excitability.

Methods

Isolated sensory neurons were treated with either short-interfering RNAs (siRNAs) or a variety of pharmacological agents targeted to S1PR₁/R₂/R₃ to determine the role(s) of these receptors in regulating neuronal excitability. The excitability of isolated sensory neurons was assessed by using whole-cell patch-clamp recording to measure the capacity of these cells to fire action potentials (APs).

Results

After siRNA treatment, exposure to S1P failed to augment the excitability. Pooled siRNA targeted to S1PR₁ and R₃ also blocked the enhanced excitability produced by S1P. Consistent with the siRNA results, pretreatment with W146 and CAY10444, selective antagonists for S1PR₁ and S1PR₃, respectively, prevented the S1P-induced increase in neuronal excitability. Similarly, S1P failed to augment excitability after pretreatment with either VPC 23019, which is a S1PR₁ and R₃ antagonist, or VPC 44116, the phosphonate analog of VPC 23019. Acute exposure (10 to 15 min) to either of the well-established functional antagonists, FTY720 or CYM-5442, produced a significant increase in the excitability. Moreover, after a 1-h pretreatment with FTY720 (an agonist for S1PR₁/R₃/R₄/R₅), neither SEW2871 (S1PR₁ selective agonist) nor S1P augmented the excitability. However, after pretreatment with CYM-5442 (selective for S1PR₁), SEW2871 was ineffective, but S1P increased the excitability of some, but not all, sensory neurons.

Conclusions

These results demonstrate that the enhanced excitability produced by S1P is mediated by activation of S1PR₁ and/or S1PR₃.

【 授权许可】

   
2015 Li et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

【 参考文献 】

• [1]Hannun YA, Obeid LM: Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008, 9:139-50.
• [2]Pyne S, Pyne NJ: New perspectives on the role of sphingosine 1-phosphate in cancer. Handb Exp Pharmacol. 2013, 216:55-71.
• [3]Maceyka M, Spiegel S: Sphingolipid metabolites in inflammatory disease. Nature. 2014, 510:58-67.
• [4]van Echten-Deckert G, Hagen-Euteneuer N, Karaca I, Walter J: Sphingosine-1-phosphate: boon and bane for the brain. Cell Physiol Biochem. 2014, 34:148-57.
• [5]Rosen H, Gonzalez-Cabrera PJ, Sanna MG, Brown S: Sphingosine 1-phosphate receptor signaling. Annu Rev Biochem. 2009, 78:743-68.
• [6]Rosen H, Germana Sanna M, Gonzalez-Cabrera PJ, Roberts E: The organization of the sphingosine 1-phosphate signaling system. Curr Top Microbiol Immunol. 2014, 378:1-21.
• [7]Welch SP, Sim-Selley LJ, Selley DE: Sphingosine-1-phosphate receptors as emerging targets for treatment of pain. Biochem Pharmacol. 2012, 84:1551-62.
• [8]Salvemini D, Doyle T, Kress M, Nicol G: Therapeutic targeting of the ceramide-to-sphingosine 1-phosphate pathway in pain. Trends Pharmacol Sci. 2013, 34:110-8.
• [9]Zhang YH, Fehrenbacher JC, Vasko MR, Nicol GD: Sphingosine-1-phosphate via activation of a G-protein-coupled receptor(s) enhances the excitability of rat sensory neurons. J Neurophysiol. 2006, 96:1042-52.
• [10]Mair N, Benetti C, Andratsch M, Leitner MG, Constantin CE, Camprubí-Robles M, et al.: Genetic evidence for involvement of neuronally expressed S1P1 receptor in nociceptor sensitization and inflammatory pain. PLoS One. 2011, 6:e17268.
• [11]Roviezzo F, Del Galdo F, Abbate G, Bucci M, D’Agostino B, Antunes E, et al.: Human eosinophil chemotaxis and selective in vivo recruitment by sphingosine 1-phosphate. Proc Natl Acad Sci U S A. 2004, 101:11170-5.
• [12]Roviezzo F, Brancaleone V, De Gruttola L, Vellecco V, Bucci M, D’Agostino B, et al.: Sphingosine-1-phosphate modulates vascular permeability and cell recruitment in acute inflammation in vivo. J Pharmacol Exp Ther. 2011, 337:830-7.
• [13]Doyle T, Finley A, Chen Z, Salvemini D: Role for peroxynitrite in sphingosine-1-phosphate-induced hyperalgesia in rats. Pain. 2011, 152:643-8.
• [14]Kays JS, Li C, Nicol GD: Expression of sphingosine 1-phosphate receptors in the rat dorsal root ganglia and defined single isolated sensory neurons. Physiol Genomics. 2012, 44:889-901.
• [15]Chi XX, Nicol GD: The sphingosine 1-phosphate receptor, S1PR1, plays a prominent but not exclusive role in enhancing the excitability of sensory neurons. J Neurophysiol. 2010, 104:2741-8.
• [16]Zhang YH, Kays J, Hodgdon KE, Sacktor TC, Nicol GD: Nerve growth factor enhances the excitability of rat sensory neurons through activation of the atypical protein kinase C isoform. PKMζ. J Neurophysiol. 2012, 107:315-35.
• [17]Holzer P: Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev. 1991, 43:143-201.
• [18]Petruska JC, Napaporn J, Johnson RD, Gu JG, Cooper BY: Subclassified acutely dissociated cells of rat DRG: histochemistry and patterns of capsaicin-, proton-, and ATP-activated currents. J Neurophysiol. 2000, 84:2365-79.
• [19]Yuan B, Latek R, Hossbach M, Tuschl T, Lewitter F: siRNA Selection Server: an automated siRNA oligonucleotide prediction server. Nucleic Acids Res 2004, 32(Web Server issue):W130-4.
• [20]Zhang YH, Vasko MR, Nicol GD: Ceramide, a putative second messenger for nerve growth factor, modulates the TTX-resistant Na+ current and delayed rectifier K+ current in rat sensory neurons. J Physiol. 2002, 544:385-402.
• [21]Li C, Chi XX, Xie W, Strong JA, Zhang JM, Nicol GD: Sphingosine 1-phosphate receptor 2 antagonist JTE-013 increases the excitability of sensory neurons independently of the receptor. J Neurophysiol. 2012, 108:1473-83.
• [22]Taiwo YO, Bjerknes LK, Goetzl EJ, Levine JD: Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system. Neuroscience. 1989, 32:577-80.
• [23]Cui M, Nicol GD: Cyclic AMP mediates the prostaglandin E2-induced potentiation of bradykinin excitation in rat sensory neurons. Neuroscience. 1995, 66:459-66.
• [24]Hingtgen CM, Waite KJ, Vasko MR: Prostaglandins facilitate peptide release from rat sensory neurons by activating the adenosine 3′,5′-cyclic monophosphate transduction cascade. J Neurosci. 1995, 15:5411-9.
• [25]Guerrero M, Poddutoori R, Urbano M, Peng X, Spicer TP, Chase PS, et al.: Discovery, design and synthesis of a selective S1P3 receptor allosteric agonist. Bioorg Med Chem Lett. 2013, 23:6346-9.
• [26]Sanna MG, Wang SK, Gonzalez-Cabrera PJ, Don A, Marsolais D, Matheu MP, et al.: Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol. 2006, 2:434-41.
• [27]Koide Y, Hasegawa T, Takahashi A, Endo A, Mochizuki N, Nakagawa M, et al.: Development of novel EDG3 antagonists using a 3D database search and their structure-activity relationships. J Med Chem. 2002, 45:4629-38.
• [28]Lichte K, Rossi R, Danneberg K, ter Braak M, Kürschner U, Jakobs KH, et al.: Lysophospholipid receptor-mediated calcium signaling in human keratinocytes. J Invest Dermatol. 2008, 128:1487-98.
• [29]Wetter JA, Revankar C, Hanson BJ: Utilization of the Tango beta-arrestin recruitment technology for cell-based EDG receptor assay development and interrogation. J Biomol Screen. 2009, 14:1134-41.
• [30]Jongsma M, Hendriks-Balk MC, Michel MC, Peters SL, Alewijnse AE: BML-241 fails to display selective antagonism at the sphingosine-1-phosphate receptor, S1P(3). Br J Pharmacol. 2006, 149:277-82.
• [31]Salomone S, Waeber C: Selectivity and specificity of sphingosine-1-phosphate receptor ligands: caveats and critical thinking in characterizing receptor-mediated effects. Front Pharmacol. 2011, 2:9.
• [32]Pyne NJ, Pyne S: Selectivity and specificity of sphingosine 1-phosphate receptor ligands: “off-targets” or complex pharmacology? Front Pharmacol. 2011, 2:26.
• [33]Long JS, Edwards J, Watson C, Tovey S, Mair KM, Schiff R, et al.: Sphingosine kinase 1 induces tolerance to human epidermal growth factor receptor 2 and prevents formation of a migratory phenotype in response to sphingosine 1-phosphate in estrogen receptor-positive breast cancer cells. Mol Cell Biol. 2010, 30:3827-41.
• [34]Mair KM, Robinson E, Kane KA, Pyne S, Brett RR, Pyne NJ, et al.: Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery. Br J Pharmacol. 2010, 161:176-92.
• [35]Davis MD, Clemens JJ, Macdonald TL, Lynch KR: Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem. 2005, 280:9833-41.
• [36]Foss FW Jr, Snyder AH, Davis MD, Rouse M, Okusa MD, Lynch KR, et al.: Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg Med Chem. 2007, 15:663-77.
• [37]Lynch KR, Macdonald TL: Sphingosine 1-phosphate chemical biology. Biochim Biophys Acta. 2008, 1781:508-12.
• [38]Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, et al.: The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002, 277:21453-7.
• [39]Billich A, Bornancin F, Dévay P, Mechtcheriakova D, Urtz N, Baumruker T: Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem. 2003, 278:47408-15.
• [40]Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S: The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett. 2003, 554:189-93.
• [41]Sanchez T, Estrada-Hernandez T, Paik JH, Wu MT, Venkataraman K, Brinkmann V, et al.: Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J Biol Chem. 2003, 278:47281-90.
• [42]Kharel Y, Lee S, Snyder AH, Sheasley-O’neill SL, Morris MA, Setiady Y, et al.: Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem. 2005, 280:36865-72.
• [43]Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, et al.: Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002, 296:346-9.
• [44]Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, et al.: Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010, 9:883-97.
• [45]Gräler MH, Goetzl EJ: The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J. 2004, 18:551-3.
• [46]Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, et al.: Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004, 427:355-60.
• [47]LaMontagne K, Littlewood-Evans A, Schnell C, O’Reilly T, Wyder L, Sanchez T, et al.: Antagonism of sphingosine-1 phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization. Cancer Res. 2006, 66:221-31.
• [48]Oo ML, Thangada S, Wu MT, Liu CH, Macdonald TL, Lynch KR, et al.: Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem. 2007, 282:9082-9.
• [49]Mullershausen F, Zecri F, Cetin C, Billich A, Guerini D, Seuwen K: Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol. 2009, 5:428-34.
• [50]Jongsma M, van Unen J, van Loenen PB, Michel MC, Peters SL, Alewijnse AE: Different response patterns of several ligands at the sphingosine-1-phosphate receptor subtype 3 (S1P3). Br J Pharmacol. 2009, 156:1305-11.
• [51]Sykes DA, Riddy D, Stamp C, Bradley M, McGuiness N, Sattikar A, et al.: Investigating the molecular mechanisms through which FTY720-P causes persistent S1P1 receptor internalisation. Br J Pharmacol. 2014, 171:4797-807.
• [52]Sensken SC, Stäubert C, Keul P, Levkau B, Schöneberg T, Gräler MH: Selective activation of G alpha i mediated signalling of S1P3 by FTY720-phosphate. Cell Signal. 2008, 20:1125-33.
• [53]Riddy DM, Stamp C, Sykes DA, Charlton SJ, Dowling MR: Reassessment of the pharmacology of Sphingosine-1-phosphate S1P3 receptor ligands using the DiscoveRx PathHunter™ and Ca2+ release functional assays. Br J Pharmacol. 2012, 167:868-80.
• [54]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.
• [55]Halmer R, Walter S, Faßbender K: Sphingolipids: important players in multiple sclerosis. Cell Physiol Biochem. 2014, 34:111-8.
• [56]Hisano Y, Kobayashi N, Kawahara A, Yamaguchi A, Nishi T: The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter of the phosphorylated form of the immunomodulating agent FTY720. J Biol Chem. 2011, 286:1758-66.
• [57]French KJ, Schrecengost RS, Lee BD, Zhuang Y, Smith SN, Eberly JL, et al.: Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 2003, 63:5962-9.
• [58]French KJ, Upson JJ, Keller SN, Zhuang Y, Yun JK, Smith CD: Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther. 2006, 318:596-603.
• [59]Orr Gandy KA, Obeid LM: Targeting the sphingosine kinase/sphingosine 1-phosphate pathway in disease: review of sphingosine kinase inhibitors. Biochim Biophys Acta. 2013, 1831:157-66.
• [60]Gonzalez-Cabrera PJ, Jo E, Sanna MG, Brown S, Leaf N, Marsolais D, et al.: Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions. Mol Pharmacol. 2008, 74:1308-18.
• [61]Gonzalez-Cabrera PJ, Cahalan SM, Nguyen N, Sarkisyan G, Leaf NB, Cameron MD, et al.: S1P1 receptor modulation with cyclical recovery from lymphopenia ameliorates mouse model of multiple sclerosis. Mol Pharmacol. 2012, 81:166-74.
• [62]Camprubí-Robles M, Mair N, Andratsch M, Benetti C, Beroukas D, Rukwied R, et al.: Sphingosine-1-phosphate-induced nociceptor excitation and ongoing pain behavior in mice and humans is largely mediated by S1P3 receptor. J Neurosci. 2013, 33:2582-892.
• [63]Pyne S, Pyne N: Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. Pharmacol Ther. 2000, 88:115-31.
• [64]Siehler S, Manning DR: Pathways of transduction engaged by sphingosine 1-phosphate through G protein-coupled receptors. Biochim Biophys Acta. 2002, 1582:94-9.
• [65]Sanchez T, Hla T: Structural and functional characteristics of S1P receptors. J Cell Biochem. 2004, 92:913-22.
• [66]Muscoli C, Doyle T, Dagostino C, Bryant L, Chen Z, Watkins LR, et al.: Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids. J Neurosci. 2010, 30:15400-8.
• [67]Xie W, Strong JA, Kays J, Nicol GD, Zhang JM: Knockdown of the sphingosine-1-phosphate receptor S1PR1 reduces pain behaviors induced by local inflammation of the rat sensory ganglion. Neurosci Lett. 2012, 515:61-5.
• [68]Coste O, Pierre S, Marian C, Brenneis C, Angioni C, Schmidt H, et al.: Antinociceptive activity of the S1P-receptor agonist FTY720. J Cell Mol Med. 2008, 12:995-1004.
• [69]Janes K, Little JW, Li C, Bryant L, Chen C, Chen Z, et al.: The development and maintenance of paclitaxel-induced neuropathic pain requires activation of the sphingosine 1-phosphate receptor subtype 1. J Biol Chem. 2014, 289:21082-97.
• [70]Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001, 29:e45.