Journal of Neural Transmission

, Volume 126, Issue 10, pp 1259–1271 | Cite as

Role of the protease-activated receptor 1 in regulating the function of glial cells within central and peripheral nervous system

  • Elena PompiliEmail author
  • Cinzia Fabrizi
  • Francesco Fornai
  • Lorenzo Fumagalli
High Impact Review in Neuroscience, Neurology or Psychiatry - Review Article


Protease-activated receptor 1 (PAR1) is a cell surface receptor, which belongs to a family of G protein-coupled receptors and signals in response to multiple extracellular proteases. PAR1 is widely distributed in mammalian cells and tissues, including human glial cells. Within this context, PAR1 may participate to various activities promoted by glial cells. In fact, glia does not represent merely a glue in the nervous system but affects significantly various neuronal functions and activities being also significantly involved in the pathophysiology of various nervous system disorders. In this review, we summarize the current understanding of PAR1 expression and functions within glial cells both in the central and peripheral nervous system.


Protease-activated receptor 1 Glial cells Central nervous system Peripheral nervous system 



Work performed in the author’s group was funded by PRIN to L.F., Sapienza University of Rome-Scientific Research Program 2018 to C.F. The authors thank Tommaso Savorani for developing the graphic figures.


  1. Almonte AG, Hamill CE, Chhatwal JP, Wingo TS, Barber JA, Lyuboslavsky PN, Sweatt JD, Ressler KJ, White DA, Traynelis SF (2007) Learning and memory deficits in mice lacking protease-activated receptor-1. Neurobiol Learn Mem 88:295–304CrossRefGoogle Scholar
  2. Almonte AG, Qadri LH, Sultan FA, Watson JA, Mount DJ, Rumbaugh G, Sweatt JD (2013) Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity. J Neurochem 124:109–122. CrossRefPubMedGoogle Scholar
  3. Bae JS, Kim YU, Park MK, Rezaie AR (2009) Concentration dependent dual effect of thrombin in endothelial cells via PAR-1 and PI3 Kinase. J Cell Physiol 219:744–751. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Balaban CD, O’Callaghan JP, Billingsley ML (1988) Trimethyltin-induced neuronal damage in the rat brain: comparative studies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins. Neuroscience 26:337–361CrossRefGoogle Scholar
  5. Balcaitis S, Xie Y, Weinstein JR, Andersen H, Hanisch UK, Ransom BR, Möller T (2003) Expression of proteinase-activated receptors in mouse microglial cells. Neuroreport 14:2373–2377CrossRefGoogle Scholar
  6. Bao X, Hua Y, Keep RF, Xi G (2018) Thrombin-induced tolerance against oxygen-glucose deprivation in astrocytes: role of protease-activated receptor-1. Cond Med 1:57–63PubMedPubMedCentralGoogle Scholar
  7. Beecher KL, Andersen TT, Fenton JW 2nd, Festoff BW (1994) Thrombin receptor peptides induce shape change in neonatal murine astrocytes in culture. J Neurosci Res 37:108–115CrossRefGoogle Scholar
  8. Boven LA, Vergnolle N, Henry SD, Silva C, Imai Y, Holden J, Warren K, Hollenberg MD, Power C (2003) Up-regulation of proteinase-activated receptor 1 expression in astrocytes during HIV encephalitis. J Immunol 170:2638–2646CrossRefGoogle Scholar
  9. Brabeck C, Michetti F, Geloso MC, Corvino V, Goezalan F, Meyermann R, Schluesener HJ (2002) Expression of EMAP-II by activated monocytes/microglial cells in different regions of the rat hippocampus after trimethyltin-induced brain damage. Exp Neurol 177:341–346CrossRefGoogle Scholar
  10. Burda JE, Radulovic M, Yoon H, Scarisbrick IA (2013) Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy. Glia 61:1456–1470. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Burda JE, Bernstein AM, Sofroniew MV (2016) Astrocyte roles in traumatic brain injury. Exp Neurol 3:305–315. CrossRefGoogle Scholar
  12. Choi MS, Kim YE, Lee WJ, Choi JW, Park GH, Kim SD, Jeon SJ, Go HS, Shin SM, Kim WK, Shin CY, Ko KH (2008) Activation of protease-activated receptor1 mediates induction of matrix metalloproteinase-9 by thrombin in rat primary astrocytes. Brain Res Bull 76:368–375. CrossRefPubMedGoogle Scholar
  13. Choi CI, Yoon H, Drucker KL, Langley MR, Kleppe L, Scarisbrick IA (2018) The thrombin receptor restricts subventricular zone neural stem cell expansion and differentiation. Sci Rep 8:9360. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Coughlin SR (2005) Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 3:1800–1814CrossRefGoogle Scholar
  15. De Luca C, Virtuoso A, Maggio N, Papa M (2017) Neuro-coagulopathy: blood coagulation factors in central nervous system diseases. Int J Mol Sci 18(pii):E2128. CrossRefPubMedGoogle Scholar
  16. De Luca C, Colangelo AM, Alberghina L, Papa M (2018) Neuro-immune hemostasis: homeostasis and diseases in the central nervous system. Front Cell Neurosci 12:459. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Debeir T, Gueugnon J, Vigé X, Benavides J (1996) Transduction mechanisms involved in thrombin receptor-induced nerve growth factor secretion and cell division in primary cultures of astrocytes. J Neurochem 66:2320–2328CrossRefGoogle Scholar
  18. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I (2018) Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173:1073–1081. CrossRefPubMedGoogle Scholar
  19. Del Bigio MR (2010) Ependymal cells: biology and pathology. Acta Neuropathol 119:55–73. CrossRefPubMedGoogle Scholar
  20. Donovan FM, Pike CJ, Cotman CW, Cunningham DD (1997) Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J Neurosci 17:5316–5326CrossRefGoogle Scholar
  21. Fabrizi C, Pompili E, Panetta B, Nori SL, Fumagalli L (2009) Protease-activated receptor-1 regulates cytokine production and induces the suppressor of cytokine signaling-3 in microglia. Int J Mol Med 24:367–371CrossRefGoogle Scholar
  22. Ferraz da Silva I, Freitas-Lima LC, Graceli JB, Rodrigues LCM (2018) Organotins in neuronal damage, brain function, and behavior: a short review. Front Endocrin (Lausanne) 8:366. CrossRefGoogle Scholar
  23. Flaumenhaft R, De Ceunynck K (2017) Targeting PAR1: now what? Trends Pharmacol Sci 38:701–716. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Franklin RJM, Ffrench-Constant C (2017) Regenerating CNS myelin–from mechanisms to experimental medicines. Nat Rev Neurosci 18:753–769. CrossRefPubMedGoogle Scholar
  25. Geloso MC, Vinesi P, Michetti F (1996) Parvalbumin-immunoreactive neurons are not affected by trimethyltin-induced neurodegeneration in the rat hippocampus. Exp Neurol 139:269–277CrossRefGoogle Scholar
  26. Geloso MC, Vinesi P, Michetti F (1997) Calretinin-containing neurons in trimethyltin-induced neurodegeneration in the rat hippocampus: an immunocytochemical study. Exp Neurol 146:67–73CrossRefGoogle Scholar
  27. Geloso MC, Corvino V, Cavallo V, Toesca A, Guadagni E, Passalacqua R, Michetti F (2004) Expression of astrocytic nestin in the rat hippocampus during trimethyltin-induced neurodegeneration. Neurosci Lett 357:103–106CrossRefGoogle Scholar
  28. Gingrich MB, Junge CE, Lyuboslavsky P, Traynelis SF (2000) Potentiation of NMDA receptor function by the serine protease thrombin. J Neurosci 20:4582–4595CrossRefGoogle Scholar
  29. Gómez-Gonzalo M, Losi G, Chiavegato A, Zonta M, Cammarota M, Brondi M, Vetri F, Uva L, Pozzan T, de Curtis M, Ratto GM, Carmignoto G (2010) An excitatory loop with astrocytes contributes to drive neurons to seizure threshold. PLoS Biol 8:e1000352. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Griffin JH, Zlokovic BV, Mosnier LO (2015) Activated protein C: biased for translation. Blood 125:2898–2907. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Gülke E, Gelderblom M, Magnus T (2018) Danger signals in stroke and their role on microglia activation after ischemia. Ther Adv Neurol Disord 11:1–14. CrossRefGoogle Scholar
  32. Gutiérrez-Venegas G, Guadarrama-Solís A, Muñoz-Seca C, Arreguín-Cano JA (2015) Hydrogen peroxide-induced apoptosis in human gingival fibroblasts. Int J Clin Exp Pathol 8:15563–15572PubMedPubMedCentralGoogle Scholar
  33. Hamill CE, Caudle WM, Richardson JR, Yuan H, Pennell KD, Greene JG, Miller GW, Traynelis SF (2007) Exacerbation of dopaminergic terminal damage in a mouse model of Parkinson’s disease by the G-protein-coupled receptor protease-activated receptor 1. Mol Pharmacol 72:653–664CrossRefGoogle Scholar
  34. Han KS, Woo J, Park H, Yoon BJ, Choi S, Lee CJ (2013) Channel-mediated astrocytic glutamate release via Bestrophin-1 targets synaptic NMDARs. Mol Brain 6:4. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Hansen DV, Hanson JE, Sheng M (2018) Microglia in Alzheimer’s disease. J Cell Biol 217:459–472. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Henrich-Noack P, Riek-Burchardt M, Baldauf K, Reiser G, Reymann KG (2006) Focal ischemia induces expression of protease-activated receptor1 (PAR1) and PAR3 on microglia and enhances PAR4 labeling in the penumbra. Brain Res 1070:232–241CrossRefGoogle Scholar
  37. Hermann GE, Van Meter MJ, Rood JC, Rogers RC (2009) Proteinase-activated receptors in the nucleus of the solitary tract: evidence for glial-neural interactions in autonomic control of the stomach. J Neurosci 29:9292–9300. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Hernández M, Bayón Y, Sánchez Crespo M, Nieto ML (1997) Thrombin produces phosphorylation of cytosolic phospholipase A2 by a mitogen-activated protein kinase kinase-independent mechanism in the human astrocytoma cell line 1321N1. Biochem J 328:263–269CrossRefGoogle Scholar
  39. Hu H, Yamashita S, Hua Y, Keep RF, Liu W, Xi G (2010) Thrombin-induced neuronal protection: role of the mitogen activated protein kinase/ribosomal protein S6 kinase pathway. Brain Res 1361:93–101. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Hu S, Wu G, Zheng J, Liu X, Zhang Y (2019) Astrocytic thrombin-evoked VEGF release is dependent on p44/42 MAPKs and PAR1. Biochem Biophys Res Commun 509:585–589. CrossRefPubMedGoogle Scholar
  41. Huda R, Chang Z, Do J, McCrimmon DR, Martina M (2018) Activation of astrocytic PAR1 receptors in the rat nucleus of the solitary tract regulates breathing through modulation of presynaptic TRPV1. J Physiol 596:497–513. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Hyung S, Jung K, Cho SR, Jeon NL (2018) The Schwann Cell as an Active Synaptic Partner. ChemPhysChem 19:1123–1127. CrossRefPubMedGoogle Scholar
  43. Ishida Y, Nagai A, Kobayashi S, Kim SU (2006) Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase. J Neuropathol Exp Neurol 65:66–77CrossRefGoogle Scholar
  44. Ishikawa K, Kubo T, Shibanoki S, Matsumoto A, Hata H, Asai S (1997) Hippocampal degeneration inducing impairment of learning in rats: model of dementia? Behav Brain Res 83:39–44CrossRefGoogle Scholar
  45. Jessen KR, Mirsky R, Lloyd AC (2015) Schwann cells: development and role in nerve repair. Cold Spring Harb Perspect Biol 7:a020487. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Junge CE, Lee CJ, Hubbard KB, Zhang Z, Olson JJ, Hepler JR, Brat DJ, Traynelis SF (2004) Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes. Exp Neurol 188:94–103CrossRefGoogle Scholar
  47. Kamato D, Mitra P, Davis F, Osman N, Chaplin R, Cabot PJ, Afroz R, Thomas W, Zheng W, Kaur H, Brimble M, Little PJ (2017) Gaq proteins: molecular pharmacology and therapeutic potential. Cell Mol Life Sci 74:1379–1390. CrossRefPubMedGoogle Scholar
  48. Kaufmann R, Patt S, Zieger M, Kraft R, Tausch S, Henklein P, Nowak G (2000) The two-receptor system PAR-1/PAR-4 mediates alpha-thrombin-induced [Ca(2 +)](i) mobilization in human astrocytoma cells. J Cancer Res Clin Oncol 126:91–94CrossRefGoogle Scholar
  49. Kidd GJ, Ohno N, Trapp BD (2013) Biology of Schwann cells. Handb Clin Neurol 115:55–79. CrossRefPubMedGoogle Scholar
  50. Lanuza MA, Besalduch N, Garcia N, Sabaté M, Santafé MM, Tomàs J (2007) Plastic-embedded semithin cross-sections as a tool for high-resolution immunofluorescence analysis of the neuromuscular junction molecules: specific cellular location of protease-activated receptor-1. J Neurosci Res 85:748–756CrossRefGoogle Scholar
  51. Laskowski A, Reiser G, Reymann KG (2007) Protease-activated receptor-1 induces generation of new microglia in the dentate gyrus of traumatised hippocampal slice cultures. Neurosci Lett 415:17–21CrossRefGoogle Scholar
  52. Lee CJ, Mannaioni G, Yuan H, Woo DH, Gingrich MB, Traynelis SF (2007) Astrocytic control of synaptic NMDA receptors. J Physiol 581:1057–1081CrossRefGoogle Scholar
  53. Lee EJ, Woo MS, Moon PG, Baek MC, Choi IY, Kim WK, Junn E, Kim HS (2010) Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J Immunol 185:615–623. CrossRefPubMedGoogle Scholar
  54. Leferink PS, Heine VM (2018) The healthy and diseased microenvironments regulate oligodendrocyte properties: implications for regenerative medicine. Am J Pathol 188:39–52. CrossRefPubMedGoogle Scholar
  55. Li Q, Zhao H, Pan P, Ru X, Zuo S, Qu J, Liao B, Chen Y, Ruan H, Feng H (2018) Nexilin regulates oligodendrocyte progenitor cell migration and remyelination and is negatively regulated by protease-activated receptor 1/ras-proximate-1 signaling following subarachnoid hemorrhage. Front. Neurol 9:282. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Ludeman MJ, Kataoka H, Srinivasan Y, Esmon NL, Esmon CT, Coughlin SR (2005) PAR1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem 280:13122–13128CrossRefGoogle Scholar
  57. Maeda S, Nakajima K, Tohyama Y, Kohsaka S (2009) Characteristic response of astrocytes to plasminogen/plasmin to upregulate transforming growth factor beta 3 (TGFbeta3) production/secretion through proteinase-activated receptor-1 (PAR-1) and the downstream phosphatidylinositol 3-kinase (PI3 K)-Akt/PKB signaling cascade. Brain Res 1305:1–13. CrossRefPubMedGoogle Scholar
  58. Maggio N, Shavit E, Chapman J, Segal M (2008) Thrombin induces long-term potentiation of reactivity to afferent stimulation and facilitates epileptic seizures in rat hippocampal slices: toward understanding the functional consequences of cerebrovascular insults. J Neurosci 28:732–736. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Malovichko MV, Sabo TM, Maurer MC (2013) Ligand binding to anion-binding exosites regulates conformational properties of thrombin. J Biol Chem 288:8667–8678. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Mannaioni G, Orr AG, Hamill CE, Yuan H, Pedone KH, McCoy KL, Berlinguer Palmini R, Junge CE, Lee CJ, Yepes M, Hepler JR, Traynelis SF (2008) Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1. J Biol Chem 283:20600–20611. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Möller T, Hanisch UK, Ransom BR (2000) Thrombin-induced activation of cultured rodent microglia. J Neurochem 75:1539–1547CrossRefGoogle Scholar
  62. Nag S (2011) Morphology and properties of astrocytes. Methods Mol Biol 686:69–100. CrossRefPubMedGoogle Scholar
  63. Nan YN, Zhu JY, Tan Y, Zhang Q, Jia W, Hua Q (2014) Staurosporine induced apoptosis rapidly downregulates TDP- 43 in glioma cells. Asian Pac J Cancer Prev 15:3575–3579CrossRefGoogle Scholar
  64. Natunen TA, Gynther M, Rostalski H, Jaako K, Jalkanen AJ (2019) Extracellular prolyl oligopeptidase derived from activated microglia is a potential neuroprotection target. Basic Clin Pharmacol Toxicol. CrossRefPubMedGoogle Scholar
  65. Nave KA, Werner HB (2014) Myelination of the nervous system: mechanisms and functions. Annu Rev Cell Dev Biol 30:503–533. CrossRefGoogle Scholar
  66. Niego B, Samson AL, Petersen KU, Medcalf RL (2011) Thrombin-induced activation of astrocytes in mixed rat hippocampal cultures is inhibited by soluble thrombomodulin. Brain Res 1381:38–51. CrossRefPubMedGoogle Scholar
  67. Nuriya M, Hirase H (2016) Involvement of astrocytes in neurovascular communication. Prog Brain Res 225:41–62. CrossRefPubMedGoogle Scholar
  68. Oh SJ, Han KS, Park H, Woo DH, Kim HY, Traynelis SF, Lee CJ (2012) Protease activated receptor 1-induced glutamate release in cultured astrocytes is mediated by Bestrophin-1 channel but not by vesicular exocytosis. Mol Brain 5:38. CrossRefPubMedPubMedCentralGoogle Scholar
  69. Okamoto T, Nishibori M, Sawada K, Iwagaki H, Nakaya N, Jikuhara A, Tanaka N, Saeki K (2001) The effects of stimulating protease-activated receptor-1 and -2 in A172 human glioblastoma. J Neural Transm (Vienna) 108:125–140CrossRefGoogle Scholar
  70. Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94:1077–1098. CrossRefGoogle Scholar
  71. Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Pisanu A, Lecca D, Mulas G, Wardas J, Simbula G, Spiga S, Carta AR (2014) Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol Dis 71:280–291. CrossRefPubMedGoogle Scholar
  73. Polavarapu R, Gongora MC, Yi H, Ranganthan S, Lawrence DA, Strickland D, Yepes M (2007) Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit. Blood 109:3270–3278CrossRefGoogle Scholar
  74. Pompili E, Nori SL, Geloso MC, Guadagni E, Corvino V, Michetti F, Fumagalli L (2004) Trimethyltin-induced differential expression of PAR subtypes in reactive astrocytes of the rat hippocampus. Brain Res Mol Brain Res 122:93–98CrossRefGoogle Scholar
  75. Pompili E, Fabrizi C, Fumagalli L (2006) PAR-1 upregulation by trimethyltin and lipopolysaccharide in cultured rat astrocytes. Int J Mol Med 18:33–39PubMedGoogle Scholar
  76. Pompili E, Fabrizi C, Nori SL, Panetta B, Geloso MC, Corvino V, Michetti F, Fumagalli L (2011) Protease-activated receptor-1 expression in rat microglia after trimethyltin treatment. J Histochem Cytochem 59:302–311. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Pompili E, Fabrizi C, Somma F, Correani V, Maras B, Schininà ME, Ciraci V, Artico M, Fornai F, Fumagalli L (2017) PAR1 activation affects the neurotrophic properties of Schwann cells. Mol Cell Neurosci 79:23–33. CrossRefPubMedGoogle Scholar
  78. Ramachandran R, Noorbakhsh F, Defea K, Hollenberg MD (2012) Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov 11:69–86. CrossRefPubMedGoogle Scholar
  79. Ransom BR, Ransom CB (2012) Astrocytes: multitalented stars of the central nervous system. Methods Mol Biol 814:3–7. CrossRefPubMedGoogle Scholar
  80. Richter-Landsberg C, Heinrich M (1996) OLN-93: a new permanent oligodendroglia cell line derived from primary rat brain glial cultures. J Neurosci Res 45:161–173CrossRefGoogle Scholar
  81. Rohl C, Sievers J (2005) Microglia is activated by astrocytes in trimethyltin intoxication. Toxicol Appl Pharm 204:36–45CrossRefGoogle Scholar
  82. Roy RV, Ardeshirylajimi A, Dinarvand P, Yang L, Rezaie AR (2016) Occupancy of human EPCR by protein C induces beta-arrestin-2 biased PAR1 signalling by both APC and thrombin. Blood 128:1884–1893. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Russo A, Soh UJ, Paing MM, Arora P, Trejo J (2009) Caveolae are required for protease-selective signaling by protease-activated receptor-1. Proc Natl Acad Sci USA 106:6393–6397. CrossRefPubMedGoogle Scholar
  84. Salter MW, Beggs S (2014) Sublime microglia: expanding roles for the guardians of the CNS. Cell 158:15–24. CrossRefPubMedGoogle Scholar
  85. Scarisbrick IA, Radulovic M, Burda JE, Larson N, Blaber SI, Giannini C, Blaber M, Vandell AG (2012) Kallikrein 6 is a novel molecular trigger of reactive astrogliosis. Biol Chem 393:355–367. CrossRefPubMedPubMedCentralGoogle Scholar
  86. Schuepbach RA, Riewald M (2010) Coagulation factor Xa cleaves protease activated receptor-1 and mediates signaling dependent on binding to the endothelial protein C receptor. J Thromb Haemost 8:379–388CrossRefGoogle Scholar
  87. Shan H, Chu Y, Chang P, Yang L, Wang Y, Zhu S, Zhang M, Tao L (2017) Neuroprotective effects of hydrogen sulfide on sodium azide-induced autophagic cell death in PC12 cells. Mol Med Rep 16:5938–5946. CrossRefPubMedPubMedCentralGoogle Scholar
  88. Shavit E, Beilin O, Korczyn AD, Sylantiev C, Aronovich R, Drory VE, Gurwitz D, Horresh I, Bar-Shavit R, Peles E, Chapman J (2008) Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block. Brain 131:1113–1122. CrossRefPubMedGoogle Scholar
  89. Shavit E, Michaelson DM, Chapman J (2011) Anatomical localization of protease-activated receptor-1 and protease-mediated neuroglial crosstalk on peri-synaptic astrocytic endfeet. J Neurochem 119:460–473. CrossRefPubMedGoogle Scholar
  90. Shavit-Stein E, Aronovich R, Sylantiev C, Gera O, Gofrit SG, Chapman J, Dori A (2019) Blocking thrombin significantly ameliorates experimental autoimmune neuritis. Front Neurol 9:1139. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Shigetomi E, Bowser DN, Sofroniew MV, Khakh BS (2008) Two forms of astrocyte calcium excitability have distinct effects on NMDA receptor-mediated slow inward currents in pyramidal neurons. J Neurosci 28:6659–6663. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Simmons S, Lee RV, Möller T, Weinstein JR (2013) Thrombin induces release of proinflammatory chemokines interleukin-8 and interferon-γ-induced protein-10 from cultured human fetal astrocytes. NeuroReport 24:36–40. CrossRefPubMedGoogle Scholar
  93. Sofroniew MV (2014) Astrogliosis. Cold Spring Harb Perspect Biol 7:a020420. CrossRefGoogle Scholar
  94. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. CrossRefPubMedGoogle Scholar
  95. Soh UJ, Trejo J (2012) Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through beta-arrestin and dishevelled-2 scaffolds. Proc Natl Acad Sci USA 108:E1372–E1380CrossRefGoogle Scholar
  96. Sokolova E, Reiser G (2008) Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: localization, expression and participation in neurodegenerative diseases. Thromb Haemost 100:576–581CrossRefGoogle Scholar
  97. Sorensen SD, Nicole O, Peavy RD, Montoya LM, Lee CJ, Murphy TJ, Traynelis SF, Hepler JR (2003) Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol Pharmacol 64:1199–1209CrossRefGoogle Scholar
  98. Striggow F, Riek-Burchardt M, Kiesel A, Schmidt W, Henrich-Noack P, Breder J, Krug M, Reymann KG, Reiser G (2001) Four different types of protease-activated receptors are widely expressed in the brain and are up-regulated in hippocampus by severe ischemia. Eur J Neurosci 4:595–608CrossRefGoogle Scholar
  99. Strokin M, Sergeeva M, Reiser G (2003) Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. Br J Pharmacol 139:1014–1022CrossRefGoogle Scholar
  100. Suo Z, Wu M, Ameenuddin S, Anderson HE, Zoloty JE, Citron BA, Andrade-Gordon P, Festoff BW (2002) Participation of protease-activated receptor-1 in thrombin-induced microglial activation. J Neurochem 80:655–666CrossRefGoogle Scholar
  101. Tritschler F, Murín R, Birk B, Berger J, Rapp M, Hamprecht B, Verleysdonk S (2007) Thrombin causes the enrichment of rat brain primary cultures with ependymal cells via protease-activated receptor 1. Neurochem Res 32:1028–1035CrossRefGoogle Scholar
  102. Ubl JJ, Reiser G (1997) Characteristics of thrombin-induced calcium signals in rat astrocytes. Glia 21:361–369CrossRefGoogle Scholar
  103. Vance KM, Rogers RC, Hermann GE (2015) PAR1-activated astrocytes in the nucleus of the solitary tract stimulate adjacent neurons via NMDA receptors. J Neurosci 35:776–785. CrossRefPubMedPubMedCentralGoogle Scholar
  104. Vandell AG, Larson N, Laxmikanthan G, Panos M, Blaber SI, Blaber M, Scarisbrick IA (2008) Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines. J Neurochem 107:855–870. CrossRefPubMedPubMedCentralGoogle Scholar
  105. Vu TK, Hung DT, Wheaton VI, Coughlin SR (1991) Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64:1057–1068CrossRefGoogle Scholar
  106. Wang H, Ubl JJ, Reiser G (2002a) Four subtypes of protease-activated receptors, co-expressed in rat astrocytes, evoke different physiological signaling. Glia 37:53–63CrossRefGoogle Scholar
  107. Wang H, Ubl JJ, Stricker R, Reiser G (2002b) Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways. Am J Physiol Cell Physiol 283:C1351–C1364CrossRefGoogle Scholar
  108. Wang Y, Richter-Landsberg C, Reiser G (2004) Expression of protease-activated receptors (PARs) in OLN-93 oligodendroglial cells and mechanism of PAR-1-induced calcium signaling. Neuroscience 126:69–82CrossRefGoogle Scholar
  109. Wang Y, Luo W, Stricker R, Reiser G (2006) Protease-activated receptor-1 protects rat astrocytes from apoptotic cell death via JNK-mediated release of the chemokine GRO/CINC-1. J Neurochem 98:1046–1060CrossRefGoogle Scholar
  110. Wang Y, Luo W, Reiser G (2007a) Proteinase-activated receptor-1 and -2 induce the release of chemokine GRO/CINC-1 from rat astrocytes via differential activation of JNK isoforms, evoking multiple protective pathways in brain. Biochem J 401:65–78CrossRefGoogle Scholar
  111. Wang Y, Luo W, Reiser G (2007b) The role of calcium in protease-activated receptor-induced secretion of chemokine GRO/CINC-1 in rat brain astrocytes. J Neurochem 103:814–819CrossRefGoogle Scholar
  112. Wang Y, Luo W, Reiser G (2007c) Activation of protease-activated receptors in astrocytes evokes a novel neuroprotective pathway through release of chemokines of the growth-regulated oncogene/cytokine-induced neutrophil chemoattractant family. Eur J Neurosci 26:3159–3168CrossRefGoogle Scholar
  113. Weinstein JR, Gold SJ, Cunningham DD, Gall CM (1995) Cellular localization of thrombin receptor mRNA in rat brain: expression by mesencephalic dopaminergic neurons and codistribution with prothrombin mRNA. J Neurosci 15:2906–2919CrossRefGoogle Scholar
  114. Weinstein JR, Ettinger RE, Zhang M, Andersen H, Hanisch UK, Möller T (2008) Thrombin regulates CD40 expression in microglial cells. Neuroreport 19:757–760. CrossRefPubMedGoogle Scholar
  115. Weinstein JR, Zhang M, Kutlubaev M, Lee R, Bishop C, Andersen H, Hanisch UK, Möller T (2009) Thrombin-induced regulation of CD95(Fas) expression in the N9 microglial cell line: evidence for involvement of proteinase-activated receptor(1) and extracellular signal-regulated kinase 1/2. Neurochem Res 34:445–452. CrossRefPubMedGoogle Scholar
  116. Yoon H, Radulovic M, Drucker KL, Wu J, Scarisbrick IA (2015) The thrombin receptor is a critical extracellular switch controlling myelination. Glia 63:846–859. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Zhao P, Metcalf M, Bunnett NW (2014) Biased signaling of protease-activated receptors. Front Endocrinol (Lausanne) 5:67. CrossRefGoogle Scholar
  118. Zhu Z, Reiser G (2014) Signaling mechanism of protease activated receptor 1-induced proliferation of astrocytes: stabilization of hypoxia inducible factor-1α triggers glucose metabolism and accumulation of cyclin D1. Neurochem Int 79:20–32. CrossRefPubMedGoogle Scholar

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© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Anatomy, Histology, Forensic Medicine and OrthopedicsSapienza University of RomeRomeItaly
  2. 2.Department of Translational Research and New Technologies in Medicine and SurgeryUniversity of PisaPisaItaly
  3. 3.IRCCS NeuromedPozzilliItaly

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