Soriano Francesc X, Hardingham Giles E
Centre for Neuroscience Research, University of Edinburgh, Edinburgh EH8 9XD, UK.
J Physiol. 2007 Oct 15;584(Pt 2):381-7. doi: 10.1113/jphysiol.2007.138875. Epub 2007 Aug 9.
The ability of Ca(2+) influx through the N-methyl d-aspartate subclass of glutamate receptor (NMDA receptor) to both kill neurons and to promote survival under different circumstances is well established. Here we discuss the signal pathways that mediate this dichotomous signalling, and the factors that influence whether an NMDA receptor-dependent Ca(2+) signal results in a net pro-survival or pro-death effect. The magnitude of NMDA receptor activation, be it intensity or duration, is of course very important in determining the nature of the response to an episode of NMDA receptor activity, with excitotoxic death pathways requiring higher levels than survival pathways. However, the NMDA receptor is not merely a conduit for Ca(2+) influx: the consequences of NMDA receptor activity can be influenced by signalling molecules that physically associate with the NMDA receptor or indeed the location (synaptic versus extrasynaptic) of the receptor. Furthermore, we discuss the possibility that the Ca(2+) effectors of survival and death are in different subcellular locations, and thus depend on the spatial characteristics of the Ca(2+) transient. A greater understanding of these issues may point to ways of selectively blocking pro-death signalling in neurological disorders such as stroke, where global NMDA receptor antagonists have proved ineffective.
钙离子通过谷氨酸受体（NMDA受体）的N-甲基-D-天冬氨酸亚类内流，在不同情况下既能杀死神经元，又能促进其存活，这一点已得到充分证实。在此，我们讨论介导这种二分信号传导的信号通路，以及影响NMDA受体依赖性钙离子信号是产生净促存活还是促死亡效应的因素。NMDA受体激活的程度，无论是强度还是持续时间，在决定对NMDA受体活性发作的反应性质方面当然非常重要，兴奋性毒性死亡通路比存活通路需要更高的水平。然而，NMDA受体不仅仅是钙离子内流的通道：NMDA受体活性的后果可能会受到与NMDA受体物理结合的信号分子的影响，实际上还会受到受体位置（突触与突触外）的影响。此外，我们讨论了存活和死亡的钙离子效应器位于不同亚细胞位置的可能性，因此取决于钙离子瞬变的空间特征。对这些问题有更深入的了解，可能会指出在中风等神经系统疾病中选择性阻断促死亡信号传导的方法，而全局NMDA受体拮抗剂已被证明无效。
