Interference of S-alkyl derivatives of glutathione with brain ionotropic glutamate receptors.
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 microM). 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-(3)H]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 gamma-glutamyl moieties.
Tampere Brain Research Center, University of Tampere Medical School, Finland.
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Jenei
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Janáky
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Varga
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Saransaari
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Oja
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002540:Cerebral Cortex / Q000737:chemistry; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D019803:Glutathione Disulfide / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D011485:Protein Binding / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000187:drug effects* / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D000097806:GluK2 Kainate Receptor
D002118:Calcium; D005978:Glutathione; D019803:Glutathione Disulfide; D008024:Ligands; D018092:Kainic Acid Receptors; D013438:Sulfhydryl Compounds; D000097806:GluK2 Kainate Receptor; C040136:glutathione sulfonate; C042431:S-ethyl glutathione; C017514:S-methyl glutathione