INTERFERENCE OF S-ALKYL DERIVATIVES OF GLUTATHIONE WITH BRAIN IONOTROPIC GLUTAMATE RECEPTORS

The effects of glutathione, glutathione sulfonate and S-alkyl derivati ves of glutathione on the binding of glutamate and selective ligands o f ionotropic N-methyl-D-aspartate (NMDA) and non-NMDA receptors were s tudied with mouse synaptic membranes. The effects of glutathione and i ts analogues on Ca-45(2+) influx were also estimated in cultured rat c erebellar granule cells. Reduced and oxidized glutathione, glutathione sulfonate, S-methyl-, -ethyl-, -propyl-, -butyl- and -pentylglutathio ne inhibited the Na+-independent binding of L-[H-3]glutamate. They str ongly inhibited also the binding of mino-3-hydroxy-5-[H-3]methyl-4-iso xazolepropionate [H-3]AMPA (IC50 values: 0.8-15.9 mu M). S-Alkylation of glutathione rendered the derivatives unable to inhibit [H-3]kainate binding. The NMDA-sensitive binding of L-[H-3]glutamate and the bindi ng of 3-[(R)- arboxypiperazin-4-yl][1,2-H-3]propyl-1-phosphonate ([H-3 ]CPP, a competitive antagonist at NMDA sites) were inhibited by the pe ptides at micromolar concentrations. The strychnine-insensitive bindin g of the NMDA coagonist [H-3]glycine was attenuated only by oxidized g lutathione and glutathione sulfonate. All peptides slightly enhanced t he use-dependent binding of [H-3]dizocilpine (MK-801) to the NMDA-gate d ionophores. This effect was additive with the effect of glycine but not with that of saturating concentrations of glutamate or glutamate p lus glycine. The glutamate- and NMDA-evoked influx of Ca-45(2+) into c erebellar granule cells was inhibited by the S-alkyl derivatives of gl utathione. We conclude that besides glutathione the endogenous S-methy lglutathione and glutathione sulfonate and the synthetic S-alkyl deriv atives of glutathione act as ligands of the AMPA and NMDA receptors. I n the NMDA receptor-ionophore these glutathione analogues bind prefera bly to the glutamate recognition site via their gamma-glutamyl moietie s.