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ISSN 1674-7992(Online)

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Front Biol    2011, Vol. 6 Issue (6) : 468-476    https://doi.org/10.1007/s11515-011-1187-6
REVIEW
NMDA receptor signaling: death or survival?
Tong LUO, Wei-Hua WU(), Bo-Shiun CHEN()
Institute of Molecular Medicine and Genetics, Department of Neurology, Georgia Health Sciences University, Augusta, GA 30912, USA
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Abstract

Glutamate-induced neuronal damage is mainly caused by overactivation of N-methyl-D-aspartate (NMDA) receptors. Conversely, normal physiological brain function and neuronal survival require adequate activation of NMDA receptors. Studies have revealed that NMDA receptor-induced neuronal death or survival is mediated through distinct subset of NMDA receptors triggering different intracellular signaling pathways. Here we discuss recent advances in the characterization of NMDA receptors in neuronal protection, emphasizing subunit-specific role, which contributes to temporal-spatial distribution, subcellular localization and diverse channel properties of NMDA receptors.
Keywords NMDA receptors      glutamate      excitotoxicity      ischemia      neuroprotection     
Corresponding Author(s): WU Wei-Hua,Email:wwu@georgiahealth.edu; CHEN Bo-Shiun,Email:bochen@georgiahealth.edu   
Issue Date: 01 December 2011
 Cite this article:   
Bo-Shiun CHEN,Tong LUO,Wei-Hua WU. NMDA receptor signaling: death or survival?[J]. Front Biol, 2011, 6(6): 468-476.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-011-1187-6
https://academic.hep.com.cn/fib/EN/Y2011/V6/I6/468
Fig.1  Distinct signaling pathways of synaptic and extrasynaptic NMDAR in neuron fate. (A) Synaptic NMDAR activity regulates gene expression to promote neuronal survivial. Synaptic NMDAR activity down-regulates the expression of pro-death genes by inhibiting forkhead box protein O (FOXO) activity though PI3K-Akt pathway. Synaptic current can also activate CaMKIV and upregulate a battery of pro-survival genes by activation of cAMP response element binding protein (CREB). (B) Extrasynaptic NMDAR signal has opposing effect on gene expression to induce neuronal death. Extrasynaptic NMDAR activity blocks CREB-dependent pro-survival gene expression. FOXOs are also targets of extrasynaptic NMDAR activity to activate expression of pro-death genes.
Fig.2  Distinct signaling pathways of synaptic and extrasynaptic NMDAR in neuron fate. A. Synaptic NMDAR activity regulates gene expression to promote neuronal survivial. Synaptic NMDAR activity down-regulates the expression of pro-death genes by inhibiting forkhead box protein O (FOXO) activity though PI3K-Akt pathway. Synaptic current can also activate CaMKIV and upregulate a battery of pro-survival genes by activation of cyclic-AMP response element binding protein (CREB). B. Extrasynaptic NMDAR signal has opposing effect on gene expression to induce neuronal death. Extrasynaptic NMDAR activity blocks CREB-dependent pro-survival gene expression. FOXOs are also targets of extrasynaptic NMDAR activity to activate expression of pro-death genes.
Fig.3  NR2C and NR3A promote neuronal survival. (A) IGF-1 or NMDA application to neurons phosphorylates serine 1096 of NR2C though PI3K-Akt pathway, which increases the surface expression of NR2C-containing NMDARs and promotes neuronal survival. (B) Overexpression of NR3A-containing NMDARs supports neuronal survival with an unknown mechanism.
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