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Interference of S-Alkyl Derivatives of Glutathione with Brain Ionotropic Glutamate Receptors

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The effects of glutathione, glutathione sulfonate and S-alkyl derivatives of glutathione on the binding of glutamate and selective ligands of ionotropic N-methyl-D-aspartate (NMDA) and non-NMDA receptors were studied with mouse synaptic membranes. The effects of glutathione and its analogues on 45Ca2+ influx were also estimated in cultured rat cerebellar granule cells. Reduced and oxidized glutathione, glutathione sulfonate, S-methyl-, -ethyl-, -propyl-, -butyl- and -pentylglutathione inhibited the Na+-independent binding of L-[3H]glutamate. They strongly inhibited also the binding of (S)-2-amino-3-hydroxy-5-[3H]methyl-4-isoxazolepropionate [3H]AMPA (IC50 values: 0.8–15.9 μM). S-Alkylation of glutathione rendered the derivatives unable to inhibit [3H]kainate binding. The NMDA-sensitive binding of L-[3H]glutamate and the binding of 3-[(R)-2-carboxypiperazin-4-yl][1,2-3H]propyl-1-phosphonate ([3H]CPP, a competitive antagonist at NMDA sites) were inhibited by the peptides at micromolar concentrations. The strychnine-insensitive binding of the NMDA coagonist [3H]glycine was attenuated only by oxidized glutathione and glutathione sulfonate. All peptides slightly enhanced the use-dependent binding of [3H]dizocilpine (MK-801) to the NMDA-gated ionophores. This effect was additive with the effect of glycine but not with that of saturating concentrations of glutamate or glutamate plus glycine. The glutamate- and NMDA-evoked influx of 45Ca2+ into cerebellar granule cells was inhibited by the S-alkyl derivatives of glutathione. We conclude that besides glutathione the endogenous S-methylglutathione and glutathione sulfonate and the synthetic S-alkyl derivatives of glutathione act as ligands of the AMPA and NMDA receptors. In the NMDA receptor-ionophore these glutathione analogues bind preferably to the glutamate recognition site via their γ-glutamyl moieties.

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Authors and Affiliations

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

    Zsolt Jenei, Réka Janáky, Vince Varga, Pirjo Saransaari & Simo S. Oja

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

    Zsolt Jenei & Vince Varga

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

    Simo S. Oja

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  1. Zsolt Jenei
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Correspondence to Vince Varga.

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Jenei, Z., Janáky, R., Varga, V. et al. Interference of S-Alkyl Derivatives of Glutathione with Brain Ionotropic Glutamate Receptors. Neurochem Res 23, 1085–1091 (1998). https://doi.org/10.1023/A:1020712203611

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