Summary

Glutamate binds to both excitatory neurotransmitter binding sites and a W-dependent, quisqualate- and cystine-inhibited transport site on brain neurons. The neuroblastoma-primary retina hybrid cells (NWRE-105) are susceptible to glutamate-induced cytotoxicity. The Cl--dependent transport site to which glutamate and quisqualate (but not kainate or NMDA) bind has a higher affinity for cystine than for glutamate. tower-ing cystine concentrations in the cell culture medium results in cytotoxicity similar to that induced by gluta-mate addition in its morphology, kinetics, and CaZ+ dependence. Glutamate-induced cytotoxicity is direct-ly proportional to its ability to inhibit cystine uptake. Exposure to glutamate (or lowered cystine) causes a de-crease in glutathione levels and an accumulation of in-tracellular peroxides. Like NW-RE-105 cells, primary rat hippocampal neurons (but not glia) in culture degener-ate in medium with lowered cystine concentration. Thus, glutamate-induced cytotoxicity in N18-RE-105 cells is due to inhibition of cystine uptake, resulting in lowered glutathione levels leading to oxidative stress and cell death