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¹ Centre for Neuroscience Research, University of Edinburgh, Edinburgh EH8 9XD, UK

The ability of Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ effectors of survival and death are in different subcellular locations, and thus depend on the spatial characteristics of the Ca²⁺ 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.

(Received 18 June 2007; accepted after revision 6 August 2007; first published online 9 August 2007)
Corresponding author G. E. Hardingham: Centre for Neuroscience Research, University of Edinburgh, Edinburgh EH8 9XD, UK. Email: giles.hardingham{at}ed.ac.uk

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