Anegawa N J, Lynch D R, Verdoorn T A, Pritchett D B
Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia 19104, USA.
J Neurochem. 1995 May;64(5):2004-12. doi: 10.1046/j.1471-4159.1995.64052004.x.
Neurons grown in culture die when they are exposed to high concentrations (0.1-1 mM) of the neurotransmitter L-glutamate. A similar phenomenon may occur in the mammalian brain during ischemia and other injuries that cause excessive glutamate release. Activation of N-methyl-D-aspartate (NMDA) receptors and the consequent Ca2+ influx are thought to play a critical role in the process of neuronal toxicity. Events subsequent to the Ca2+ influx are not well understood. We have discovered that nonneuronal kidney cells expressing NMDA receptors after DNA transfection undergo cell death unless they are protected by drugs that block the NMDA receptor ion channel. Furthermore, transfected cells expressing a mutated NMDA receptor that conducts less Ca2+ are less vulnerable to cell death. In addition, we find that even though several active forms of NMDA receptors can be synthesized in these cells after transfection with different cloned subunits, not all receptor types are equally toxic. These experiments suggest that Ca2+ influx through NMDA channels may be toxic to nonneuronal cells and that the NMDA receptor expression may be the major neuron-specific component of excitotoxicity.
在体外培养条件下生长的神经元，当暴露于高浓度（0.1 - 1 mM）的神经递质L - 谷氨酸时会死亡。在哺乳动物大脑中，类似的现象可能发生在缺血及其他导致谷氨酸过度释放的损伤过程中。N - 甲基 - D - 天冬氨酸（NMDA）受体的激活以及随之而来的Ca2+内流被认为在神经元毒性过程中起关键作用。Ca2+内流之后发生的事件目前还不太清楚。我们发现，DNA转染后表达NMDA受体的非神经元肾细胞会发生细胞死亡，除非它们受到能阻断NMDA受体离子通道的药物保护。此外，表达传导较少Ca2+的突变型NMDA受体的转染细胞对细胞死亡的敏感性较低。另外，我们发现，尽管用不同的克隆亚基转染这些细胞后可以合成几种活性形式的NMDA受体，但并非所有受体类型的毒性都相同。这些实验表明，通过NMDA通道的Ca2+内流可能对非神经元细胞有毒性，并且NMDA受体表达可能是兴奋性毒性中主要的神经元特异性成分。
