The Role of GluN2A in Cerebral Ischemia: Promoting Neuron Death and Survival in the Early Stage and Thereafter

Over-activation of NMDA receptors is a crucial step required for brain damage following a stroke. Although clinical trials for NMDA receptor blockers have failed, the role of GluN2A subunit in cerebral ischemia has been extensively evaluated in recent years. However, the effect of GluN2A on neuron damage induced by cerebral ischemia remains a matter of controversy. The underlying reason may be that GluN2A mediates both pro-death and pro-survival effects. These two effects result from two mutually excluding pathways, Ca 2+ overload-dependent pro-death signaling and C-terminal-dependent pro-survival signaling, respectively. During the early stage of cerebral ischemia, over-activation of GluN2A plays an important role in Ca 2+ overload. Under this condition, pro-death signaling might overcome pro-survival signaling. When GluN2A activity is restored almost to the normal level over time, pro-survival signaling of GluN2A will be dominant. The hypothesis that GluN2A promotes neuron death and survival in the early stage of cerebral ischemia and thereafter will be introduced in detail in this review.