Compartmentalized NMDA receptor signalling to survival and death.
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.
Soriano
Francesc X
FX
Centre for Neuroscience Research, University of Edinburgh, Edinburgh EH8 9XD, UK.
Hardingham
Giles E
GE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate
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