Deletion of P2X7 Receptor Decreases Basal Glutathione Level by Changing Glutamate-Glutamine Cycle and Neutral Amino Acid Transporters.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Author(s): Park H;Park H; Kim JE; Kim JE
  • Source:
    Cells [Cells] 2020 Apr 16; Vol. 9 (4). Date of Electronic Publication: 2020 Apr 16.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI
    • Subject Terms:
      Amino Acid Transport Systems, Neutral/*metabolism ; Glutamic Acid/*metabolism ; Glutamine/*metabolism ; Glutathione/*metabolism ; Receptors, Purinergic P2X7/*metabolism; Acetylcysteine/pharmacology ; Amino Acid Transport System ASC/metabolism ; Animals ; Gene Deletion ; Glutamate-Ammonia Ligase/metabolism ; Hippocampus/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Minor Histocompatibility Antigens/metabolism ; Molsidomine/analogs & derivatives ; Molsidomine/pharmacology ; Receptors, Purinergic P2X7/genetics
    • Abstract:
      Glutathione (GSH) is an endogenous tripeptide antioxidant that consists of glutamate-cysteine-glycine. GSH content is limited by the availability of glutamate and cysteine. Furthermore, glutamine is involved in the regulation of GSH synthesis via the glutamate-glutamine cycle. P2X7 receptor (P2X7R) is one of the cation-permeable ATP ligand-gated ion channels, which is involved in neuronal excitability, neuroinflammation and astroglial functions. In addition, P2X7R activation decreases glutamate uptake and glutamine synthase (GS) expression/activity. In the present study, we found that P2X7R deletion decreased the basal GSH level without altering GSH synthetic enzyme expressions in the mouse hippocampus. P2X7R deletion also increased expressions of GS and ASCT2 (a glutamine:cysteine exchanger), but diminished the efficacy of N-acetylcysteine (NAC, a GSH precursor) in the GSH level. SIN-1 (500 μM, a generator nitric oxide, superoxide and peroxynitrite), which facilitates the cystine-cysteine shuttle mediated by xCT (a glutamate/cystein:cystine/NAC antiporter), did not affect basal GSH concentration in WT and P2X7R knockout (KO) mice. However, SIN-1 effectively reduced the efficacy of NAC in GSH synthesis in WT mice, but not in P2X7R KO mice. Therefore, our findings indicate that P2X7R may be involved in the maintenance of basal GSH levels by regulating the glutamate-glutamine cycle and neutral amino acid transports under physiological conditions, which may be the defense mechanism against oxidative stress during P2X7R activation.
    • References:
      Biochem Biophys Res Commun. 1995 Sep 5;214(1):125-30. (PMID: 7545389)
      Front Mol Neurosci. 2019 Aug 07;12:183. (PMID: 31440138)
      Neurobiology (Bp). 1999;7(4):461-77. (PMID: 10897806)
      J Neurochem. 2003 Nov;87(4):891-901. (PMID: 14622120)
      Neurotherapeutics. 2016 Jan;13(1):217-25. (PMID: 26572666)
      Oxid Med Cell Longev. 2018 Aug 30;2018:4235695. (PMID: 30228854)
      Eur J Pharmacol. 2003 Oct 31;479(1-3):237-47. (PMID: 14612154)
      J Cell Sci. 2009 Jan 1;122(Pt 1):136-44. (PMID: 19066285)
      Biochem Soc Trans. 2001 Nov;29(Pt 6):717-22. (PMID: 11709062)
      J Neurosci. 2015 May 6;35(18):7143-52. (PMID: 25948264)
      J Histochem Cytochem. 2006 May;54(5):549-57. (PMID: 16399997)
      Cell Death Dis. 2014 Aug 07;5:e1362. (PMID: 25101675)
      Clin Nutr. 2003 Dec;22(6):515-22. (PMID: 14613752)
      Glia. 2016 Feb;64(2):227-39. (PMID: 26469940)
      Neurosci Lett. 2007 Mar 19;415(1):45-8. (PMID: 17222973)
      Cell Death Dis. 2018 May 10;9(5):546. (PMID: 29749377)
      Brain Res. 2008 Jan 16;1189:12-22. (PMID: 18048013)
      Glia. 2006 Dec;54(8):873-9. (PMID: 16998864)
      Glia. 2014 Oct;62(10):1671-86. (PMID: 24895290)
      Biochem J. 2002 Sep 15;366(Pt 3):745-55. (PMID: 12057008)
      Anal Biochem. 1990 Nov 1;190(2):360-5. (PMID: 2291479)
      Glia. 2000 Oct;32(1):1-14. (PMID: 10975906)
      Prog Neurobiol. 2000 Dec;62(6):649-71. (PMID: 10880854)
      J Comp Neurol. 2016 Apr 1;524(5):1015-32. (PMID: 26494316)
      Am J Physiol Cell Physiol. 2003 Feb;284(2):C571-81. (PMID: 12529254)
      Redox Biol. 2018 Apr;14:566-575. (PMID: 29132128)
      Neurochem Res. 2010 Aug;35(8):1231-8. (PMID: 20437093)
      Biochem Biophys Res Commun. 2005 Jan 14;326(2):371-7. (PMID: 15582588)
      J Neurochem. 2008 Apr;105(1):151-64. (PMID: 18067549)
      Brain Res Bull. 2018 Mar;137:120-131. (PMID: 29183693)
      Biochim Biophys Acta. 2015 Jul;1853(7):1636-45. (PMID: 25862406)
      Epilepsy Behav. 2015 Jul;48:4-14. (PMID: 26037843)
      Free Radic Biol Med. 2007 May 15;42(10):1506-16. (PMID: 17448897)
      J Neurochem. 1999 Nov;73(5):2184-94. (PMID: 10537079)
      J Clin Invest. 2011 May;121(5):2037-47. (PMID: 21505260)
      Nat Rev Neurosci. 2009 Aug;10(8):561-72. (PMID: 19571793)
      J Neurochem. 2009 Jan;108(2):372-83. (PMID: 19012749)
      Glia. 2015 May;63(5):877-93. (PMID: 25630251)
      Free Radic Biol Med. 2004 Sep 1;37(5):607-19. (PMID: 15288119)
      PLoS One. 2013;8(3):e57626. (PMID: 23472093)
      Mol Pharmacol. 1998 Jul;54(1):207-12. (PMID: 9658207)
      Int J Mol Sci. 2018 Apr 12;19(4):. (PMID: 29649168)
      PLoS One. 2014 Jun 18;9(6):e97452. (PMID: 24940871)
      J Biol Chem. 1998 Nov 13;273(46):30713-8. (PMID: 9804846)
      Neurochem Res. 2015 Dec;40(12):2570-82. (PMID: 25428182)
      Cell Signal. 2005 Nov;17(11):1384-96. (PMID: 15985361)
      Respir Physiol Neurobiol. 2011 Dec 15;179(2-3):314-25. (PMID: 21982752)
      Am J Physiol Cell Physiol. 2008 Apr;294(4):C1012-20. (PMID: 18287333)
      PLoS One. 2014 Oct 13;9(10):e110185. (PMID: 25310682)
      Neurochem Int. 2006 May-Jun;48(6-7):611-5. (PMID: 16516348)
      Neuron. 2017 Oct 11;96(2):402-413.e5. (PMID: 29024663)
      Neuropharmacology. 2019 May 1;149:1-12. (PMID: 30695710)
      Nat Neurosci. 2006 Jan;9(1):119-26. (PMID: 16311588)
      J Biol Chem. 1996 Jun 21;271(25):14883-90. (PMID: 8662767)
      Purinergic Signal. 2017 Dec;13(4):467-478. (PMID: 28707031)
      J Neuroinflammation. 2010 Oct 12;7:65. (PMID: 20939924)
      Neuroscience. 2013 Oct 10;250:520-35. (PMID: 23876319)
    • Contributed Indexing:
      Keywords: GCLC; GSH; GSH synthetase; GSS; NAC; SIN-1; cysteine; glutamate cysteine ligase
    • Accession Number:
      0 (Amino Acid Transport System ASC)
      0 (Amino Acid Transport Systems, Neutral)
      0 (Minor Histocompatibility Antigens)
      0 (Receptors, Purinergic P2X7)
      0 (Slc1a5 protein, mouse)
      0RH81L854J (Glutamine)
      3KX376GY7L (Glutamic Acid)
      5O5U71P6VQ (linsidomine)
      D46583G77X (Molsidomine)
      EC 6.3.1.2 (Glutamate-Ammonia Ligase)
      GAN16C9B8O (Glutathione)
      WYQ7N0BPYC (Acetylcysteine)
    • Publication Date:
      Date Created: 20200423 Date Completed: 20210305 Latest Revision: 20210305
    • Publication Date:
      20231215
    • Accession Number:
      PMC7226967
    • Accession Number:
      10.3390/cells9040995
    • Accession Number:
      32316268