Skip to main content
Log in

Purinergic signaling and microglia

  • Invited Review
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

Microglial cells are considered as the pathologic sensors of the brain. In this paper, we review mechanisms of purinergic signaling in microglia. As ATP is not only considered as a physiological signaling substance but is also elevated in pathology, it is not surprising that microglia express a variety of P2X, P2Y and adenosin receptors. As a rapid physiological event, ATP triggers a cationic conductance, increases the potassium conductance and also elicits a calcium response. As a long-term effect, purinergic receptor activation is linked to the movement of microglial processes and, in the context of pathology, to chemotaxis. The purinoreceptors also modulate the release of substances from microglia, such as cytokines, nitric oxide, or superoxide, which are important in the context of a pathologic response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kettenmann and Ransom (eds) (2005) Neuroglia. Oxford University Press, New York

    Google Scholar 

  2. Haas S, Brockhaus J, Verkhratsky A, Kettenmann H (1996) ATP-induced membrane currents in ameboid microglial acutely isolated from mouse brain slices. Neuroscience 75(1):257–261

    Article  PubMed  CAS  Google Scholar 

  3. Boucsein C, Zacharias R, Farber K, Pavlovic S, Hanisch UK, Kettenmann H (2003) Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur J Neurosci 17(11):2267–2276

    Article  PubMed  Google Scholar 

  4. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758

    Article  PubMed  CAS  Google Scholar 

  5. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318

    Article  PubMed  CAS  Google Scholar 

  6. Walz W, Ilschner S, Ohlemeyer C, Banati R, Kettenmann H (1993) Extracellular ATP activates a cation conductance and a K+ conductance in cultured microglial cells from mouse brain. J Neurosci 13(10):4403–4411

    PubMed  CAS  Google Scholar 

  7. Illes P, Norenberg W, Gebicke-Haerter PJ (1996) Molecular mechanism of microglial activation. B. Voltage- and purinoreceptor-operated channels in microglia. Neurochem Int 29(1):13–24

    Article  PubMed  CAS  Google Scholar 

  8. Norenberg W, Cordes A, Blohbaum G, Frohlich R, Illes P (1997) Coexistence of purino-and pyrimidinoreceptors on activated rat microglial cells. Br J Pharmacol 121(6):1087–1098

    Article  PubMed  CAS  Google Scholar 

  9. Chakfe Y, Seguin R, Antel JP, Morissette C, Malo D, Henderson D, Seguela P (2002) ADP and AMP induce interleukin-1 beta release from microglia cells through activation of ATP-primed P2X7 receptor channels. J Neurosci 22(8):3061–3069

    PubMed  Google Scholar 

  10. Möller T, Kann O, Verkhratsky A, Kettenmann H (2000) Activation of mouse microglial cells affects P2 receptor signaling. Brain Res 853(1):49–59

    Article  PubMed  Google Scholar 

  11. Hoffmann A, Kann O, Ohlemeyer C, Hanisch UK, Kettenmann H (2003) Elevation of basal intracellular calcium as a central element in the activation of brain macrophages (microglia): suppression of receptor-evoked calcium signaling and control of release function. J Neurosci 23(11):4410–4419

    PubMed  CAS  Google Scholar 

  12. Xiang Z, Burnstock G (2005) Expression of P2X receptors on rat microglial cells during early development. Glia 52(11):119–126

    Article  PubMed  Google Scholar 

  13. Bianco F, Fumagalli M, Pravettoni E, DAmbrosi N, Volonte C, Matteoli M, Abbraccchio MP, Verderio C (2005) Pathophysiological roles of extracellular nucleotides in glial cells: differential expression of purinergic receptors in resting and activated microglia. Brain Res Brain Res Rev 48(2):144–156

    Article  PubMed  CAS  Google Scholar 

  14. Sasaki Y, Hoshi M, Akazawa C, Nakamura Y, Tsuzuki H, Inoue K, Kohsaka S (2003) Selective expression of Gi/o-coupled ATP receptor P2Y12 in microglia in rat brain. Glia 44(3):242–250

    Article  PubMed  Google Scholar 

  15. Braun N, Sevigny J, Robson SC, Enjyoji K, Guckelberger O, Hammer K, Di Virgilio F, Zimmermann H (2000) Assignment of ecto-nucleoside triphosphate diphosphohydrolase-1/cd39 expression to microglia and vasculature of the brain. Eur J Neurosci 12:4357–4366

    Article  PubMed  CAS  Google Scholar 

  16. Schoen SW, Graeber MB, Kreutzberg GW (1992) 5′-Nucleotidase immunoreactivity of perineural microglia responding to rat facial nerve axotomy. Glia 6:314–317

    Article  PubMed  CAS  Google Scholar 

  17. Gebicke-Haerter PJ, Christoffel F, Timmer J, Northoff H, Berger M, Van Calker D (1996) Both adenosine A1- and A2-receptors are required to stimulate microglial proliferation. Neurochem Int 29(1):37–42

    Article  PubMed  CAS  Google Scholar 

  18. Hammarberg C, Schulte G, Fredholm BB (2003) Evidence for functional adenosine A3 receptors in microglia cells. J Neurochem 86(4):1051–1054

    Article  PubMed  CAS  Google Scholar 

  19. Wollmer MA, Lucius R, Wilms H, Held-Feindt J, Sievers J, Mentlein R (2001) ATP and adenosine induce ramification of microglia in vitro. J Neuroimmunol 115(1–2):19–27

    Article  PubMed  CAS  Google Scholar 

  20. Honda S, Sasaki Y, Ohsawa K, Imai Y, Nakamura Y, Inoue K, Kohsaka S (2001) Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J Neurosci 21(6):1975–1982

    PubMed  CAS  Google Scholar 

  21. Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ (1990) Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247:470–473

    Article  PubMed  CAS  Google Scholar 

  22. Guthri PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB (1999) ATP release from astrocytes mediated glial calcium waves. J Neurosci 19(2):520–528

    Google Scholar 

  23. Cotrina ML, Lin JH, Nedergaard M (1998) Cytoskeletal assembly and ATP release regulate astrocytic calcium signaling. J Neurosci 18:8794–8804

    PubMed  CAS  Google Scholar 

  24. Giaume C, Venance L (1998) Intercellular calcium signaling and gap junctional communication in astrocytes. Glia 24(1):50–64

    Article  PubMed  CAS  Google Scholar 

  25. Schipke CG, Boucsein C, Ohlemeyer C, Kirchhoff F, Kettenmann H (2002) Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices. FASEB J 16(2):255–257

    PubMed  CAS  Google Scholar 

  26. Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K, Nakata Y (2000) Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J Neurochem 75(3):965–972

    Article  PubMed  CAS  Google Scholar 

  27. Suzuki T, Hide I, Ido K, Kohsaka S, Inoue K, Nakata Y (2004) Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J Neurosci 24(1):1–7

    Article  PubMed  CAS  Google Scholar 

  28. Inoue K (2002) Microglial activation by purines and pyrimidines. Glia 40(2):156–163

    Article  PubMed  Google Scholar 

  29. Ferrari D, Stroh C, Schulze-Osthoff K (1999) P2X7/P2Z purinoreceptor-mediated activation of transcription factor NFAT in microglial cells. J Biol Chem 274(19):13205–13210

    Article  PubMed  CAS  Google Scholar 

  30. Ferrari D, Wesselborg S, Bauer MK, Schulze-Osthoff K (1997) Extracellular ATP activates transcription factor NF-kappaB through the P2Z purinoreceptor by selectively targeting NF-kappaB p65. J Cell Biol 139(7):1635–1643

    Article  PubMed  CAS  Google Scholar 

  31. Brough D, LeFeuvre RA, Iwakura Y, Rothwell NJ (2002) Purinergic (P2X7) receptor activation of microglia induces cell death via an interleukin-1-independent mechanism. Mol Cell Neurosci 19(2):272–280

    Article  PubMed  CAS  Google Scholar 

  32. Sanz JM, Di Virgilio F (2000) Kinetics and mechanism of ATP-dependent IL-1-beta release from microglial cells. J Immunol 164(9):4893–4898

    PubMed  CAS  Google Scholar 

  33. Seo DR, Kim KY, Lee Yb (2004) Interleukin-10 expression in lipopolysaccharide-activated microglia is mediated by extracellular ATP in an autocrine fashion. Neuroreport 15(7):1157–1161

    Article  PubMed  CAS  Google Scholar 

  34. Ogata T, Chuai M, Morino T, Yamamoto H, Nakamura Y, Schubert P (2003) Adenosine triphosphate inhibits cytokine release from lipopolysaccharide-activated microglia via P2Y receptors. Brain Res 981(1–2):174–183

    Article  PubMed  CAS  Google Scholar 

  35. Brautigam VM, Fraiser C, Mikodemova M, Watters JJ (2005) Purinergic receptor modulation of BV-2 microglial cell activity: potential involvement of p38 MAP kinase and CREB. J Neuroimmunol 166(1–2):113–125

    Article  PubMed  CAS  Google Scholar 

  36. Lee JY, Jhun BS, Oh YT, Lee JH, Choe W, Baik HH, Ha J, Yoon KS, Kim SS, Kang I (2006) Activation of adenosine A(3) receptor suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of PI13-kinase/Akt and NF-kappaB activation in murine BV2 microglial cells. Neurosci Lett 396(1):1–6

    Article  PubMed  CAS  Google Scholar 

  37. Franke H, Gunther A, Grosche J, Schmidt R, Rossner S, Reinhardt R, Faber-Zuschratter H, Schneider D, Illes P (2004) P2X7 receptor expression after ischemia in the cerebral cortex of rats. J Neuropathol Exp Neurol 63(7):686–699

    PubMed  CAS  Google Scholar 

  38. Tanaka S, Suzuki K, Watanabe M, Matsuda A, Tone S, Koike T (1998) Upregulation of a new microglial gene, mrf-1, in response to programmed neuronal cell death and degeneration. J Neurosci 18:6358–6369

    PubMed  CAS  Google Scholar 

  39. Tanaka S, Koike T (2002) Selective inflammatory stimulations enhance release of microglial response factor (MRF)-1 from cultured microglia. Glia 40(3):260–371

    Article  Google Scholar 

  40. Kaya N, Tanaka S, Koike T (2002) ATP selectively suppresses the synthesis of the inflammatory protein microglial response factor (MRF)-1 through Ca2+ influx via P2X7 receptors in cultured microglia. Brain Res 952(1):86–97

    Article  PubMed  CAS  Google Scholar 

  41. Witting A, Walter L, Moller J, Stella N (2004) P2X7 receptors control 2-arachidonoylglycerol production by microglial cells. Proc Natl Acad Sci USA 101(9):3214–3219

    Article  PubMed  CAS  Google Scholar 

  42. Parvathenani LK, Tertyshnikova S, Greco CR, Roberts SB, Robertson B, Posmantur R (2003) P2X7 mediates superoxide production in primary microglia and is upregulated in a transgenic mouse model of Alzheimer’s disease. J Biol Chem 278(15):13309–13317

    Article  PubMed  CAS  Google Scholar 

  43. Heese K, Fiebich BL, Bauer J, Otten U (1997) Nerve growth factor (NGF) expression in rat microglia is induced by adenoseine A2a-receptors. Neurosci Lett 231(2):83–86

    Article  PubMed  CAS  Google Scholar 

  44. Fiebich BL, Biber K, Lieb K, van Calker D, Berger M, Bauer J, Gebicke-Harter PJ (1996) Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors. Glia 18(2):152–160

    Article  PubMed  CAS  Google Scholar 

  45. Brown DR, Schmidt B, Kretzschmar HA (1996) Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 380:345–347

    Article  PubMed  CAS  Google Scholar 

  46. Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374:647–650

    Article  PubMed  CAS  Google Scholar 

  47. Pyo H, Chung S, Jou I, Gwag B, Joe EH (1997) Expression and function of outward K channels induced by lipopolysaccharide in microglia. Mol Cell 7(5):610–614

    CAS  Google Scholar 

  48. Jou I, Pyo H, Chung S, Jung SY, Gwag BJ, Joe EH (1998) Expression of Kv1.5 K channels in activated microglia in vivo. Glia 24(4):408–414

    Article  PubMed  CAS  Google Scholar 

  49. Kust BM, Biber K, van Calker D, Gebicke-Haerter PJ (1999) Regulation of K channel mRNA expression by stimulation of adenosine A2a-receptors in cultured rat microglia. Glia 25(2):120–130

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank the Deutsche Forschungsgemeinschaft (SFB 507) and Bundesministerium für Bildung und Forschung (DLR 01GZ0304) for support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Helmut Kettenmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Färber, K., Kettenmann, H. Purinergic signaling and microglia. Pflugers Arch - Eur J Physiol 452, 615–621 (2006). https://doi.org/10.1007/s00424-006-0064-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-006-0064-7

Keywords

Navigation