Skip to main content
SpringerLink
Log in

Glutathione Is an Endogenous Ligand of Rat Brain N-Methyl-D-Aspartate (NMDA) and 2-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionate (AMPA) Receptors

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

A study was made of the effects of reduced (GSH) and oxidized (GSSG) glutathione on the Na+-independent and N-methyl-D-aspartate (NMDA) displaceable bindings of glutamate, on the binding of kainate, 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and ligands of the brain NMDA receptor-ionophore complex: glycine, dizocilpine (MK-801) and (±)-3-(2-car-boxypiperazin-4-yl)propyl-1-phosphonate (CPP). GSH and GSSG strongly inhibited the binding of glutamate, CPP and AMPA, kainate and glycine binding being less affected. Both peptides enhanced the binding of dizocilpine in a time- and concentration-dependent manner. This activatory effect was not additive to that of saturating concentrations of glutamate or glutamate plus glycine. The activation of dizocilpine binding by GSH and GSSG was prevented by the competitive NMDA and glycine antagonists DL-2-amino-5-phosphonovalerate and 7-chlorokynurenate. GSH and GSSG may be endogenous ligands of AMPA and NMDA receptors, binding preferably to the glutamate recognition site via their γ-glutamyl moieties. In addition to this, at millimolar concentrations they may regulate the redox state of the NMDA receptor-ionophore complex.

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. Rothman, S. M., and Olney, J. W. 1987. Excitotoxicity and the NMDA receptor. Trends Neurosci. 10:299–302.

    Google Scholar 

  2. Levy, D. I., Sucher, N. J., and Lipton S. A. 1991. Glutathione prevents N-methyl-D-aspartate receptor-mediated neurotoxicity. Neuroreport 2:345–347.

    Google Scholar 

  3. Seeburg, P. H. 1993. The TINS/TIPS lecture. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci. 16:359–365.

    Google Scholar 

  4. Collingridge, G. L., and Lester, A. J. 1989. Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol. Rev. 40:143–210.

    Google Scholar 

  5. Nakanishi, S. 1992. Molecular diversity of glutamate receptors and implications for brain function. Science 258:597–603.

    Google Scholar 

  6. Kiskin, N. I., Kristhal, O. A., Tsyndrenko, A. Y., and Akaike, N. 1986. Are sulfhydryl groups essential for function of the glutamate-operated receptor-ionophore complex? Neurosci. Lett. 66: 305–310.

    Google Scholar 

  7. Terramani, T., Kessler, M., Lynch, G., and Baudry, M. 1988. Effects of thiol-reagents on [3H]α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding to rat telencephalic membranes. Mol. Pharmacol. 34:117–123.

    Google Scholar 

  8. Lazarewicz, J. W., Wroblewski, J. T., Palmer, M. E., and Costa, E. 1989. Reduction of disulfide bonds activates NMDA-sensitive glutamate receptors in primary cultures of cerebellar granule cells. Neurosci. Res. Commun. 4:91–97.

    Google Scholar 

  9. Tang, L.-H., and Aizenman, E. 1993. Long-lasting modification of the N-methyl-D-aspartate receptor channel by a voltage-dependent sulfhydryl redox process. Mol. Pharmacol. 44:473–478.

    Google Scholar 

  10. Varga, V., Török, K., Feuer, L., Gulyás, J., and Somogyi, J. 1985. γ-Glutamyl-transferase in the brain and its role in formation of γ-L-glutamyl-taurine. Pages 115–125, in: Oja, S. S., Ahtee, L., Kontro, P., and Paasonen, M. K. (eds.), Taurine: Biological Actions and Clinical Perspectives, Alan R. Liss, New York.

    Google Scholar 

  11. Varga, V., Janáky, R., Marnela, K.-M, Gulyás, J., Kontro, P., and Oja, S. S. 1989. Displacement of excitatory amino acid receptor ligands by acidic oligopeptides. Neurochem. Res. 14:1223–1227.

    Google Scholar 

  12. Varga, V., Marnela, K.-M., Kontro, P., Gulyás, J., Vadász, Z., Lähdesmäki, P., and Oja, S. S. 1987. Effects of acidic dipeptides on aminoacidergic neurotransmission in the brain. Pages 357–368, in: Huxtable, R. J., Franconi, F., and Giotti, A. (eds.), The Biology of Taurine. Methods and Mechanisms, Plenum Press, New York.

    Google Scholar 

  13. Varga, V., Janáky, R., Holopainen, I., Kontro, P., and Oja, S. S. 1989. Effect of glutamyltaurine on calcium influx in cultured cerebellar granule cells. Pages 141–145. in: Pasantes-Morales, H., Martin, D., Shain, W., and Martin del Rio, R. (eds.), Taurine: Functional Neurochemistry, Physiology, and Cardiology, Wiley-Liss, New York.

    Google Scholar 

  14. Varga, V., Janáky, R., and Oja, S. S. 1992. Modulation of glutamate agonist-induced influx of calcium into neurons by γ-L-glutamyl and β-L-aspartyl dipeptides. Neurosci. Lett. 139:270–274.

    Google Scholar 

  15. Varga, V., Janáky, R., Marnela, K.-M., Saransaari, P., and Oja, S. S. 1994. Interactions of γ-L-glutamyltaurine with excitatory aminoacidergic neurotransmission. Neurochem. Res. 19:243–248.

    Google Scholar 

  16. Varga, V., Janáky, R., Saransaari, P., and Oja, S. S. 1994. Endogenous γ-L-glutamyl and β-L-aspartyl peptides and excitatory aminoacidergic neurotransmission in the brain. Neuropeptides 27:19–26.

    Google Scholar 

  17. Gilbert, K. R., Aizenmann, E., and Reynolds, I. J. 1991. Oxidized glutathione modulates N-methyl-D-aspartate-and depolarization-induced increases in intracellular Ca2+ in cultured rat forebrain neurons. Neurosci. Lett. 133:11–14.

    Google Scholar 

  18. Leslie, S. W., Brown, L. M., Trent, R. D., Lee, Y.-H., Morris, J. L, Jones, T. W., Randall, P. K., Lau, S. S., and Monks, T. J. 1991. Stimulation of N-methyl-D-aspartate receptor-mediated calcium entry into dissociated neurons by reduced and oxidized glutathione. Mol. Pharmacol. 41:308–314.

    Google Scholar 

  19. Janáky, R., Varga, V., Saransaari, P., and Oja, S. S. 1993. Glutathione modulates the N-methyl-D-aspartate receptor-activated calcium influx into cultured rat cerebellar granule cells. Neurosci. Lett. 156:153–157.

    Google Scholar 

  20. Orlowski, M., and Karkowsky, A. 1976. Glutathione metabolism and some possible functions of glutathione in the nervous system. Int. Rev. Neurobiol. 19:75–121.

    Google Scholar 

  21. Meister, A., and Anderson, M.E. 1983. Glutathione. Annu. Rev. Biochem. 52:711–760.

    Google Scholar 

  22. Ogita, K., and Yoneda, Y. 1987. Possible presence of [3H]glutathione (GSH) binding sites in synaptic membranes from rat brain. Neurosci. Res. 4:486–496.

    Google Scholar 

  23. Ogita, K., and Yoneda, Y. 1988. Temperature-dependent and-independent apparent binding activities of [3H]glutathione in brain synaptic membranes. Brain. Res. 463:37–46.

    Google Scholar 

  24. Ogita, K., and Yoneda, Y. 1989. Selective potentiation by L-cysteine of apparent binding activity of [3H]glutathione in synaptic membranes of rat brain. Biochem. Pharmacol. 38:1499–1505.

    Google Scholar 

  25. Guo, N., McIntosh, C., and Shaw, C. 1992. Glutathione: new candidate neuropeptide in the central nervous system. Neuroscience 51:835–842.

    Google Scholar 

  26. Lanius, R. A., Shaw, C. A., Wagey, R., and Krieger, C. 1994. Characterization, distribution, and protein kinase C-mediated regulation of [35S]glutathione binding sites in mouse and human spinal cord. J. Neurochem. 63:155–160.

    Google Scholar 

  27. Ogita, K., Kitago, T., Nakamuta, H., Fukuda, Y., Koida, M., Ogawa, Y., and Yoneda, Y. 1986. Glutathione-induced inhibition of Na+-independent and-dependent bindings of L-[3H]glutamate in rat brain. Life Sci. 39:2411–2418.

    Google Scholar 

  28. Oja, S. S., Varga, V., Janáky, R., Kontro, P., Aarnio, T., and Marnela, K.-M. 1988. Glutathione and glutamatergic neurotransmission in the brain. Pages 75–78, in: Cavalheiro E. A., Lehmann J., and Turski L. (eds.), Frontiers in Excitatory Amino Acid Research, Alan R. Liss, New York.

    Google Scholar 

  29. Sucher, N. J., and Lipton, S. A. 1991. Redox modulatory site of the NMDA receptor-channel complex: regulation by oxidized glutathione. J. Neurosci. Res. 30:582–591.

    Google Scholar 

  30. Jones, S. M., Snell, L. D., and Johnson, K. M. 1989. Characterization of the binding of radioligands to the N-methyl-D-aspartate, phencyclidine, and glycine receptors in buffy coat membranes. J. Pharmacol. Meth. 21:161–168.

    Google Scholar 

  31. Kontro, P., and Oja, S. S. 1987. Taurine and GABA binding in mouse brain: effects of freezing, washing and Triton X-100 treatment on membranes. Int. J. Neurosci. 32:881–889.

    Google Scholar 

  32. Ogita, K., and Yoneda, Y. 1990. Temperature-independent binding of [3H](±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid in brain synaptic membranes treated by Triton X-100. Brain Res. 515:51–56.

    Google Scholar 

  33. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–275.

    Google Scholar 

  34. London, E. D., and Coyle, J. T. 1979. Specific binding of [3H]kainic acid to receptor sites in rat brain. Mol. Pharmacol. 15:492–505.

    Google Scholar 

  35. Murphy, D. E., Snowhill, E. W., and Williams, W. 1987. Characterization of quisqualate recognition sites in rat brain tissue using DL-[3H]α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and a filtration assay. Neurochem. Res. 12:775–782.

    Google Scholar 

  36. Bristow, D. R., Bowery, N. G., and Woodruff, G. N. 1986. Light microscopic autoradiographic localisation of [3H]glycine and [3H]strychnine binding sites in rat brain. Eur. J. Pharmacol. 126: 303–307.

    Google Scholar 

  37. Reynolds, I. J., Murphy, S. N., and Miller, R. J. 1987. 3H-Labeled MK-801 binding to the excitatory amino acid receptor complex from rat brain is enhanced by glycine. Proc. Natl. Acad. Sci. USA 84:7744–7748.

    Google Scholar 

  38. Liu, Y. F., and Quirion R. 1992. Modulatory role of glutathione on μ-opioid, substance P/neurokinin-1, and kainic acid receptor binding sites. J. Neurochem. 59:1024–1032.

    Google Scholar 

  39. Yoneda, Y., Ogita, K., Kouda, T., and Ogawa, Y. 1990. Radioligand labeling of N-methyl-D-aspartic acid (NMDA) receptors by [3H](±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid in brain synaptic membranes treated with Triton X-100. Biochem. Pharmacol. 39:225–228.

    Google Scholar 

  40. Danysz, W., Fadda, E., Wroblewski, J. T., and Costa, E. 1989. Different modes of action of 3-amino-1-hydroxy-2-pyrrolidone (HA-966) and 7-chlorokynurenic acid in the modulation of N-methyl-D-aspartate-sensitive glutamate receptors. Mol. Pharmacol. 36:912–916.

    Google Scholar 

  41. Pullan, L. M., and Cler, J. A. 1989. Schild plot analysis of glycine and kynurenic acid at the N-methyl-D-aspartate excitatory amino acid receptor. Brain Res. 497:59–63.

    Google Scholar 

  42. Ogita, K., Enomoto, R., Nakahara, F., Ishitsubo, N., and Yoneda, Y. 1995. A possible role of glutathione as an endogenous agonist at the N-methyl-D-aspartate recognition domain in rat brain. J. Neurochem. 64:1088–1096.

    Google Scholar 

  43. Guo, N., and Shaw, C. 1992. Characterization and localization of glutathione binding sites on cultured astrocytes. Mol. Brain Res. 15:207–215.

    Google Scholar 

  44. Köhr, G., Eckardt, S., Lüddens, H., Monyer, H., and Seeburg P. H. 1994. NMDA receptor channels: subunit-specific potentiation by reducing agents. Neuron 12:1031–1040.

    Google Scholar 

  45. Globus, M. Y. T., Busto, R., Martinez, E., Valdes, I., Dietrich, W. D., and Ginsberg, M. D. 1991. Comparative effect of transient global ischemia on extracellular levels of glutamate, glycine and γ-aminobutyric acid in vulnerable and nonvulnerable brain regions in the rat. J. Neurochem. 57:470–478.

    Google Scholar 

  46. Andiné, P., Orwar, O., Jacobson, I., Sandberg, M., and Hagberg, H. 1991. Extracellular acidic sulfur-containing amino acids and γ-glutamyl peptides in global ischemia: postischemic recovery of neuronal activity is paralleled by a tetrodotoxin-sensitive increase in cysteine sulfinate in the CA1 of the rat hippocampus. J. Neurochem. 57:230–236.

    Google Scholar 

  47. Zängerle, L., Cuénod, M., Winterhalter, K. H., and Do, K. Q. 1992. Screening of thiol compounds: depolarization-induced release of glutathione and cysteine from rat brain slices. J. Neurochem. 59:181–189.

    Google Scholar 

  48. Choi, D. W. 1988. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634.

    Google Scholar 

  49. Meldrum, B., and Garthwaite, J. 1990. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol. Sci. 11:379–387.

    Google Scholar 

  50. Nicoll, R. A., Malenka, R. C., and Kauer, J. A. 1990. Functional comparison of neurotransmitter receptor subtypes in mammalian central nervous system. Physiol. Rev. 70:513–565.

    Google Scholar 

  51. Nowak, L., Bregetovski, P., Ascher, P., Herbert, A., and Prochiantz, A. 1984. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307:462–465.

    Google Scholar 

  52. Honda, K., Komoda, Y., and Inoué, S. 1994. Oxidized glutathione regulates physiological sleep in unrestrained rats. Brain Res. 636:253–258.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Tampere Brain Research Center, University of Tampere Medical School, Box 607, FIN-33101, Tampere, Finland

    V. Varga, Zs. Jenei, R. Janáky, P. Saransaari & S. S. Oja

  2. Department of Animal Physiology, Kossuth Lajos University of Sciences, Box 18, H-4010, Debrecen, Hungary

    V. Varga & Zs. Jenei

  3. Department of Clinical Physiology, Tampere University Hospital, Box 2000, FIN-33521, Tampere, Finland

    S. S. Oja

Authors
  1. V. Varga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zs. Jenei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Janáky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Saransaari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. S. Oja
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Varga, V., Jenei, Z., Janáky, R. et al. Glutathione Is an Endogenous Ligand of Rat Brain N-Methyl-D-Aspartate (NMDA) and 2-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionate (AMPA) Receptors. Neurochem Res 22, 1165–1171 (1997). https://doi.org/10.1023/A:1027377605054

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1027377605054

Search

Navigation