Skip to main content
SpringerLink
Log in

Roles of P2X7 Receptor in Glial and Neuroblastoma Cells: The Therapeutic Potential of P2X7 Receptor Antagonists

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Recently, one of the P2 purinergic receptors, the P2X7 receptor, has been extensively studied in nervous system and important functions have been revealed in both astrocytes and microglia. Stimulation of the receptors induces a sustained and nondesensitized increase in intracellular Ca2+ concentration ([Ca2+]i). In astrocytes purinergic receptors primarily regulate neurotransmission by inducing gliotransmitters release whereas in microglia the receptors stimulate the processing and release of proinflammation cytokines such as interleukin-1 and are thereby involved in inflammation and neurodegeneration. Thus, P2X7 receptors are considered not only to exert physiological functions but also mediate cell death. P2X7 receptors have also been identified in various cancer cells and in neuroblastoma cells. In these cells, the P2X7 receptor-mediated sustained Ca2+ signal is important in maintaining cellular viability and growth. Accordingly, these findings not only lead to a better understanding of roles of the receptor but also prompt the development of more potent, selective and safer P2X7 selective antagonists. These emerging antagonists bring new hope in the treatment of inflammatory-induced neurodegenerative diseases as well as neuroblastoma.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Burnstock G (1997) The past, present and future of purine nucleotides as signaling molecules. Neuropharmacology 36:1127–1139

    Article  CAS  PubMed  Google Scholar 

  2. Newman EA (2003) New roles for astrocytes: regulation of synaptic transmission. Trend Neurosci 26:536–542

    Article  CAS  PubMed  Google Scholar 

  3. El-Moatassim C, Dubyak GR (1993) Dissociation of the poreforming and phospholipase D activities stimulated via P2Z purinergic receptors in BAC1.2F5 macrophages. J Biol Chem 268:15571–15578

    CAS  PubMed  Google Scholar 

  4. Steinberg TH, Newmann AS, Swanson JA, Silverstein SC (1987) Extracellular ATP42 promotes cation fluxes in the J774 in the mouse macrophage cell line. J Biol Chem 262:8884–8888

    Google Scholar 

  5. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067

    CAS  PubMed  Google Scholar 

  6. Surprenant A, Rassendren F, Kawashima E, North RA, Buell G (1996) The cytolytic P2z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272:735–738

    Article  CAS  PubMed  Google Scholar 

  7. Ferrari D, Villalba M, Chiozzi P, Falzoni S, Ricciardi-Castagnoli P, DiVirgilio F (1996) Mouse microglia cells express a plasma membrane pore gated by extracellular ATP. J Immunol 156:1531–1539

    CAS  PubMed  Google Scholar 

  8. Ballerini P, Rathbone MP, Di Lorio P, Renzetti A, Giuliani P, D’Alimonte I, Trubiani O, Caciagli F, Ciccarelli R (1996) Rat astroglial P2Z (P2X7) receptors regulate intracellular calcium and purine release. NeuroReport 7:2533–2537

    Article  CAS  PubMed  Google Scholar 

  9. Nobile M, Monaldi I, Alloisio S, Cugnoli C, Ferroni S (2003) ATP-induced, sustained calcium signalling in cultured rat cortical astrocytes: evidence for a non-capacitative, P2X7-like-mediated calcium entry. FEBS Lett 538:71–76

    Article  CAS  PubMed  Google Scholar 

  10. Sun SH, Lin L-B, Hung AC, Kuo J-S (1999) ATP-stimulated Ca2+ influx and phospholipase D activities of a rat brain-derived type-2 astrocyte cell line, RBA-2, are mediated through P2X7 receptors. J Neurochem 73:334–343

    Article  CAS  PubMed  Google Scholar 

  11. Duechars SA, Atkinson L, Brooke RE, Musa H, Milligan CJ, Batten TFC, Buckley NJ, Parson SH, Deuchars J (2001) Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous system. J Neurosci 21:7143–7152

    Google Scholar 

  12. Williams N, Coleman PS (1982) Exploring the adenine nucleotide binding sites on mitochondrial F1-ATPase with a new photoaffinity probe, 3'-O-(4-benzoyl)benzoyl adenosine 5'-tri-phosphate. J Biol Chem 257:2834–2841

    CAS  PubMed  Google Scholar 

  13. Gonzalez FA, Ahmed AH, Lustig KD, And EL, Weisman GA (1989) Permeabilization of transformed mouse fibroblasts by 3'-O-(4-benzoyl)benzoyl adenosine 5'-triphosphate and the desensitization of the process. J Cell Physiol 139:109–115

    Article  CAS  PubMed  Google Scholar 

  14. Baraldi PG, Di Virgilio F, Romagnoli R (2004) Agonists and antagonists acting at P2X7 receptor. Curr Top Med Chem 4:1707–1717

    Article  CAS  PubMed  Google Scholar 

  15. Harden TK, Boyer JL, Nicholas RA (1995) P2-purinergic receptors: subtype-associated signaling responses and structure. Annu Rev Pharmacol Toxicol 35:541–579

    Article  CAS  PubMed  Google Scholar 

  16. Boarder MR, Hourani SMO (1998) The regulation of vascular function by P2 receptors: multiple sites and multiple receptors. Trends Pharmacol Sci 19:99–107

    Article  CAS  PubMed  Google Scholar 

  17. Murgial M, Hanaug S, Pizzol P, Rippag M, Di Virgio F (1993) Oxidized ATP. J Biol Chem 266:8199–8203

    Google Scholar 

  18. Lo J-C, Huang W-C, Chou YC, Tseng CH, Lee WL, Sun SH (2008) Activation of P2X7 receptors decreases glutamate uptake and glutamine synthetase activity in RBA-2 astrocytes via distinct mechanisms. J Neurochem 105:151–164

    Article  CAS  PubMed  Google Scholar 

  19. Sluyter R, Shemon AN, Wiley JS (2004) Glu496 to Ala polymorphism in the P2X7 receptor impairs ATP-induced IL-1 release from human monocytes. J Immunol 172:3399–3405

    CAS  PubMed  Google Scholar 

  20. Duan S, Anderson CM, Keung EC, Chen Y, Chen Y, Swanson RA (2003) P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci 23:1320–1328

    CAS  PubMed  Google Scholar 

  21. Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1b release by the ATP-gated P2X7 receptor. EMBO J 25:5071–5082

    Article  CAS  PubMed  Google Scholar 

  22. Bruzzone R, Hormuzdi SG, Barbe MT, Herb A, Monyer H (2003) Pannexins, a family of gap junction proteins expressed in brain. PNAS 100:13644–13649

    Article  CAS  PubMed  Google Scholar 

  23. Stout CE, Costantin JL, Naus CCG, Charles AC (2002) Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem 277:10482–10488

    Article  CAS  PubMed  Google Scholar 

  24. Ye Z-C, Wyeth MS, Baltan-Tekkok S, Ransom BR (2003) Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci 23:3588–3596

    CAS  PubMed  Google Scholar 

  25. Suadicani SO, Brosnan CF, Scemes E (2006) P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J Neurosci 26:1378–1385

    Article  CAS  PubMed  Google Scholar 

  26. Wilkin GP, Marriott DR, Cholewinski AJ (1990) Astrocyte heterogeneity. Trends Neurosci 13:43–46

    Article  CAS  PubMed  Google Scholar 

  27. Wang C-M, Chang Y-Y, Kuo J-S, Sun SH (2002) Activation of P2X7 receptors induced [3H]GABA release from RBA-2 type-2 astrocyte cell line through a Cl-/HCO3-dependent mechanism. Glia 37:8–18

    Article  PubMed  Google Scholar 

  28. Anderson CM, Bergher JP, Swanson RA (2004) ATP-induced ATP release from astrocytes. J Neurochem 88:246–256

    Article  CAS  PubMed  Google Scholar 

  29. Virginio C, Church D, North RA, Surprenant A (1997) Effects of divalent cations, protons and calmidazolium at the rat P2X7 receptor. Neurophannacology 36:1285–1294

    Article  CAS  Google Scholar 

  30. Le Feuvre R, Brough D, Rothwell N (2002) Extracellular ATP and P2X7 receptors in neurodegeneration. Eur J Pharmacol 447:261–269

    Article  PubMed  Google Scholar 

  31. Ferrari D, Chiozzi P, Falzoni S, Dal SM, Melchiorri L, Baricordi OR, Di Virgilio F (1997) Extracellular ATP triggers IL-1β release by activating the purinergic P2Z receptor of human macrophages. J Immunol 159:1451–1458

    CAS  PubMed  Google Scholar 

  32. Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, Griffiths RJ, Gabel CA (2001) Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 276:125–132

    Article  CAS  PubMed  Google Scholar 

  33. Ferrari D, Chiozzi P, Falzoni S, Dal SM, Collo G, Buell G, Di Virgilio F (1997) ATP-mediated cytotoxicity in microglial cells. Neuropharmacology 36:1295–1301

    Article  CAS  PubMed  Google Scholar 

  34. Chakfe Y, Seguin R, Antel JP, Morissette C, Malo D, Henderson D, Séguéla P (2002) ADP and AMP induce interleukin-1β release from microglial cells through activation of ATP-primed P2X7 receptor channel. J Neurosci 22:3061–3069

    PubMed  Google Scholar 

  35. Gudipaty L, Munetz J, Verhoef PA, Dubyak GR (2003) Essential role for Ca2+ in regulation of IL-1β secretion by P2X7 nucleotide receptor in monocytes, macrophages, and HEK-293 cells. Am J Physiol Cell Physiol 285:C286–C299

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. Song S-L, Chueh S-H (1996) Antagonistic effect of Na+ and Mg2+ on P2z purinoceptor-associated pores in dibutyryl cyclic AMP-differentiated NG108-15 cells. J Neurochem 67:1694–1701

    CAS  PubMed  Google Scholar 

  38. Larsson KP, Hansen AJ, Steen D (2002) The human SH-SY5Y neuroblastoma cell-line expresses a functional P2X7 purinoceptor that modulates voltage-dependent Ca2+ channel function. J Neurochem 83:285–298

    Article  CAS  PubMed  Google Scholar 

  39. Raffaghello L, Chiozzi P, Falzoni S, Di Virgillio F, Pistoia V (2006) The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism. Cancer Res 66:907–914

    Article  CAS  PubMed  Google Scholar 

  40. Resta V, Novelli E, Di Virgilio F, Galli-Resta L (2005) Neuronal death induced by endogenous extracellular ATP in retinal cholinergic neuron density control. Development 132:2873–2882

    Article  CAS  PubMed  Google Scholar 

  41. Adinolfi E, Melchiorri L, Falzoni S, Chiozzi P, Morelli A, Tieghi A, Cuneo A, Castoldi G, Di Virgilio F, Baricordi OR (2009) P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia. Blood 99:706–708

    Article  Google Scholar 

  42. Baricordi OR, Melchiorri L, Adinolfi E, Falzoni S, Chiozzi P, Buell G, Di Virgilio F (1999) Increased proliferation rate of lymphoid cells transfected with the P2X7 ATP receptor. J Biol Chem 274:33206–33208

    Article  CAS  PubMed  Google Scholar 

  43. Slater M, Danieletto S, Gidley-Baird A, Teh LC, Barden JA (2004) Early prostate cancer detected using expression of non-functional cytolytic P2X7 receptors. Histopathology 44:206–215

    Article  CAS  PubMed  Google Scholar 

  44. Díaz-Hernández M, Del Puerto A, Diaz-Hernandez JI, Diez-Zaera M, Lucas JJ, Garrido JJ, Miras-Portugal MT (2008) Inhibition of the ATP-gated P2X7 receptor promotes axonal growth and branching in cultured hippocampal neurons. J Cell Sci 121:3717–3728

    Article  PubMed  CAS  Google Scholar 

  45. Wu PY, Lin YC, Chang CL, Lu HT, Chin CH, Hsu TT, Chu D, Sun SH (2009) Functional decreases in P2X7 receptors are associated with retinoic acid-induced neuronal differentiation of Neuro-2a neuroblastoma cells. Cell Signal 21:881–891

    Article  CAS  PubMed  Google Scholar 

  46. Nagasawa K, Escartin C, Swanson RA (2009) Astrocyte cultures exhibit P2X7 receptor channel opening in the absence of exogenous ligands. Glia 57:622–633

    Article  PubMed  Google Scholar 

  47. Gómez-Villafuertes R, del Puerto A, Díaz-Hernández M, Bustillo D, Díaz-Hernández JI, Huerta PG, Artalejo AR, Garrido JJ, Miras-Portugal MT (2009) Ca2+/calmodulin-dependent kinase II signalling cascade mediates P2X7 receptor-dependent inhibition of neuritogenesis in neuroblastoma cells. FEBS J 276:5307–5325

    Article  PubMed  CAS  Google Scholar 

  48. Alcaraz L, Baxter A, Bent J, Bowers K, Braddock M, Cladingboel D, Donald D, Fagura M, Furber M, Laurent C, Lawson M, Mortimore M, McCormick M, Roberts N, Robertson M (2003) Novel P2X7 receptor antagonists. Bioorg Med Chem Lett 13:4043–4046

    Google Scholar 

  49. Stokes L, Jiang L-H, Alcaraz L, Bent A, Bowers K, Fagura M, Furber M, Mortimore M, Lawson M, Theaker J, Laurent C, Braddock M, Surprenant A (2006) Characterization of a selective and potent antagonist of human P2X7 receptors, AZ11645373. Br J Pharmacol 149:880–887

    Article  CAS  PubMed  Google Scholar 

  50. Honore P, Donnelly-Roberts D, Namovic MT, Hsieh G, Zhu CZ, Mikusa JP, Hernandez G, Zhong C, Gauvin DM, Chandran P, Harris R, Medrano AP, Carroll W, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF (2006) A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2, 2-dimethylpropyl)-2-(3, 4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. J Pharmacol Exp Therapeu 319:1376–1385

    Article  CAS  Google Scholar 

  51. Donnelly-Roberts DL, Jarvis MF (2007) Discovery of P2X7 receptor-selective antagonists offers new insights into P2X7 receptor function and indicates a role in chronic pain states. Br J Pharmacol 151:571–579

    Article  CAS  PubMed  Google Scholar 

  52. Florjancic AS, Peddi S, Perez-Medrano A, Li B, Namovic MT, Grayson G, Donnelly-Roberts DL, Jarvis MF, Carroll WA (2008) Synthesis and in vitro activity of 1-(2, 3-dichlorophenyl)-N-(pyridin-3-ylmethyl)-1H-1, 2, 4-triazol-5-amine and 4-(2, 3-dichlorophenyl)-N-(pyridin-3-ylmethyl)-4H-1, 2, 4-triazol-3-amine P2X7 antagonists. Bioorganic Med Chem Letters 18:2089–2092

    Article  CAS  Google Scholar 

  53. Broom DC, Matson DJ, Bradshaw E, Buck ME, Meade R, Coombs S, Matchett M, Ford KK, Yu W, Yuan J, Sun SH, Ochoa R, Krause JE, Wustrow DJ, Cortright DN (2008) CharacterizationN-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide (AACBA), a P2X7 antagonist in animal models of pain and inflammation. J Pharmacol Exp Ther 327:620–633

    Article  CAS  PubMed  Google Scholar 

  54. Matute C, Torre I, Pérez-Cerdá F, Pérez-Samartín A, Alberdi E, Etxebarria E, Arranz AM, Ravid R, Rodríguez-Antigüedad A, Sánchez-Gómez MV, Domercq M (2007) P2X7 receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J Neurosci 27:9525–9533

    Article  CAS  PubMed  Google Scholar 

  55. Wang X, Arcuino G, Takano T, Lin J, Peng WG, Wan P, Li P, Xu Q, Liu SQ, Goldman SA, Nedergaard M (2004) P2X7 receptor inhibition improves recovery after spinal cord injury. Nat Med 10:821–827

    Article  CAS  PubMed  Google Scholar 

  56. Peng W, Cotrina ML, Han X, Yu H, Bekar L, Blum L, Takano T, Tian G-F, Goldman SA, Nedergaard M (2009) Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. PNAS 106:12489–12493

    Article  CAS  PubMed  Google Scholar 

  57. Jiang L-H, Mackenzie AB, North RA, Surprenant A (2000) Brilliant blue G selectively blocks ATP-gated rat P2X7 receptors. Mol Pharmacol 58:82–88

    CAS  PubMed  Google Scholar 

  58. Beigi RD, Kertesy SB, Aquilina G, Dubyak GR (2003) Oxidized ATP (oATP) attenuates proinflammatory signaling via P2 receptor-independent mechanisms. Br J Pharmacol 140:507–519

    Article  CAS  PubMed  Google Scholar 

  59. Chen HB, Sun SH (2006) Oxidized ATP (oATP) decreases β-actin expression and intracellular superoxide concentrations in RBA-2 type 2 astrocytes independently of P2X7 receptor. Eur J Pharmacol 550:1–7

    Article  CAS  PubMed  Google Scholar 

  60. Ferrari D, Pizzirani C, Adinolfi E, Lemoli L, Curti A, Idzko M, Panther E, Di Virgilio F (2006) The P2X7 receptor: a key player in IL-1 processing and release. J Immunol 176:3877–3883

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Neuroscience, National Yang Ming University, Taipei, Taiwan, Republic of China

    Synthia H. Sun

Authors
  1. Synthia H. Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Synthia H. Sun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, S.H. Roles of P2X7 Receptor in Glial and Neuroblastoma Cells: The Therapeutic Potential of P2X7 Receptor Antagonists. Mol Neurobiol 41, 351–355 (2010). https://doi.org/10.1007/s12035-010-8120-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-010-8120-x

Keyword

Search

Navigation