TRANSFECTION OF N-METHYL-D-ASPARTATE RECEPTORS IN A NONNEURONAL CELL-LINE LEADS TO CELL-DEATH

Neurons grown in culture die when they are exposed to high concentrati ons (0.1-1 mM) of the neurotransmitter L-glutamate. A similar phenomen on may occur in the mammalian brain during ischemia and other injuries that cause excessive glutamate release. Activation of N-methyl-D-aspa rtate (NMDA) receptors and the consequent Ca2+ influx are thought to p lay a critical role in the process of neuronal toxicity. Events subseq uent to the Ca2+ influx are not well understood. We have discovered th at nonneuronal kidney cells expressing NMDA receptors after DNA transf ection undergo cell death unless they are protected by drugs that bloc k the NMDA receptor ion channel. Furthermore, transfected cells expres sing a mutated NMDA receptor that conducts less Ca2+ are less vulnerab le to cell death. In addition, we find that even though several active forms of NMDA receptors can be synthesized in these cells after trans fection with different cloned subunits, not all receptor types are equ ally toxic. These experiments suggest that Ca2+ influx through NMDA ch annels may be toxic to nonneuronal cells and that the NMDA receptor ex pression may be the major neuron-specific component of excitotoxicity.