Glutathione modulates the N-methyl-D-aspartate receptor-activated calcium influx into cultured rat cerebellar granule cells.

The effects of reduced (GSH) and oxidized (GSSG) glutathione and dithiothreitol (DTT) and L-cysteine on the influx of 45Ca2+ were studied with cultured cerebellar granule cells. DTT slightly enhanced the basal influx but strongly activated the influx stimulated by glutamate or N-methyl-D-aspartate (NMDA). The effects on the kainate- or quisqualate-induced influx were less pronounced. Extracellular GSH had no effect on the basal influx of Ca2+. A concentration of 0.5 mM GSH slightly activated the glutamate- and NMDA-induced influx while GSSG was inhibitory. The enhancement by DTT and cysteine of the responses to excitatory amino acids was attenuated by GSH and GSSG. We propose that both the accessibility and redox state of the functional sulfhydryl groups in NMDA receptor-ionophores may be regulated by endogenous glutathione. These effects are attributed to the gamma-glutamyl moiety and sulfhydryl group in the tripeptide molecule.