GLUTAMATE-RECEPTOR ION-CHANNEL PROPERTIES PREDICT VULNERABILITY TO CYTOTOXICITY IN A TRANSFECTED NONNEURONAL CELL-LINE

Excessive activation of glutamate receptors is thought to play a criti cal role in neuronal excitotoxicity. To compare the cytotoxic potentia l of different glutamate receptor subtypes and correlate receptor biop hysical properties with cytotoxicity, we have expressed recombinant re ceptors in human embryonic kidney 293 (HEK-293) cells. Survival of tra nsfected cells was analyzed under conditions of defined agonist concen tration and exposure time. For HEK-293 cells transfected with N-methyl -D-aspartate (NMDA) receptors, the EC(50) for NMDA-induced cytotoxicit y was 300 mu M. Experiments using ion substitution, or cells expressin g mutant NMDA receptors with low calcium permeability, suggested that both calcium and sodium influx through NMDA receptors contributed to c ytotoxicity. In contrast, cytotoxicity was not observed in cells trans fected with calcium permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazo le propionate- or kainate-type glutamate receptors even at saturating agonist concentrations, unless inhibitors of agonist-dependent desensi tization were included. These results directly demonstrate that calciu m permeability and desensitization kinetics play important roles in de termining the excitotoxic potential of different glutamate receptor su btypes.