Involvement of the GluN2A and GluN2B Subunits in Synaptic and Extrasynaptic N-methyl-D-aspartate Receptor Function and Neuronal Excitotoxicity

被引:126
作者
Zhou, Xianju [1 ,2 ,3 ]
Ding, Qi [1 ]
Chen, Zhuoyou [3 ]
Yun, Huifang [4 ]
Wang, Hongbing [1 ,2 ]
机构
[1] Michigan State Univ, Dept Physiol, E Lansing, MI 48824 USA
[2] Michigan State Univ, Neurosci Program, E Lansing, MI 48824 USA
[3] Nanjing Med Univ, Affiliated Hosp, Changzhou Peoples Hosp 2, Dept Neurol, Changzhou 213003, Peoples R China
[4] Nanjing Med Univ, Affiliated Hosp, Changzhou Peoples Hosp 2, Dept Anesthesiol, Changzhou 213003, Peoples R China
基金
美国国家卫生研究院;
关键词
LONG-TERM POTENTIATION; NMDA RECEPTOR; IN-VITRO; CELL-DEATH; DEVELOPMENTAL-CHANGES; DEPENDENT REGULATION; HIPPOCAMPAL-NEURONS; DIFFERENTIAL ROLES; CORTICAL-NEURONS; NR2B SUBUNITS;
D O I
10.1074/jbc.M113.482000
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
GluN2A and GluN2B are the major subunits of functional NMDA receptors (NMDAR). Previous studies have suggested that GluN2A and GluN2B may differentially mediate NMDAR function at synaptic and extrasynaptic locations and play opposing roles in excitotoxicity, such as neurodegeneration triggered by ischemic stroke and brain injury. By using pharmacological and molecular approaches to suppress or enhance the function of GluN2A and GluN2B in cultured cortical neurons, we examined NMDAR-mediated, bidirectional regulation of prosurvival signaling (i.e. the cAMP response element-binding protein (CREB)-Bdnf cascade) and cell death. Inhibition of GluN2A or GluN2B attenuated the up-regulation of prosurvival signaling triggered by the activation of either synaptic or extrasynaptic NMDAR. Inhibition of GluN2A or GluN2B also attenuated the down-regulation of prosurvival signaling triggered by the coactivation of synaptic and extrasynaptic receptors. The effects of GluN2B on CREB-Bdnf signaling were larger than those of GluN2A. Consistently, compared with suppression of GluN2A, suppression of GluN2B resulted in more reduction of NMDA- and oxygen glucose deprivation-induced excitotoxicity as well as NMDAR-mediated elevation of intracellular calcium. Moreover, excitotoxicity and down-regulation of CREB were exaggerated in neurons overexpressing GluN2A or GluN2B. Together, we found that GluN2A and GluN2B are involved in the function of both synaptic and extrasynaptic NMDAR, demonstrating that they play similar rather than opposing roles in NMDAR-mediated bidirectional regulation of prosurvival signaling and neuronal death.
引用
收藏
页码:24151 / 24159
页数:9
相关论文
共 58 条
[1]
Nurr1 Protein Is Required for N-Methyl-D-aspartic Acid (NMDA) Receptor-mediated Neuronal Survival [J].
Barneda-Zahonero, Bruna ;
Servitja, Joan-Marc ;
Badiola, Nahuai ;
Minano-Molina, Alfredo J. ;
Fado, Rut ;
Saura, Carlos A. ;
Rodriguez-Alvarez, Jose .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (14) :11351-11362
[2]
NMDA receptors Recent insights and clinical correlations [J].
Benarroch, Eduardo E. .
NEUROLOGY, 2011, 76 (20) :1750-1757
[3]
Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation [J].
Berberich, S ;
Punnakkal, P ;
Jensen, V ;
Pawlak, V ;
Seeburg, PH ;
Hvalby, O ;
Köhr, G .
JOURNAL OF NEUROSCIENCE, 2005, 25 (29) :6907-6910
[4]
Loss of GluN2B-Containing NMDA Receptors in CA1 Hippocampus and Cortex Impairs Long-Term Depression, Reduces Dendritic Spine Density, and Disrupts Learning [J].
Brigman, Jonathan L. ;
Wright, Tara ;
Talani, Giuseppe ;
Prasad-Mulcare, Shweta ;
Jinde, Seiichiro ;
Seabold, Gail K. ;
Mathur, Poonam ;
Davis, Margaret I. ;
Bock, Roland ;
Gustin, Richard M. ;
Colbran, Roger J. ;
Alvarez, Veronica A. ;
Nakazawa, Kazu ;
Delpire, Eric ;
Lovinger, David M. ;
Holmes, Andrew .
JOURNAL OF NEUROSCIENCE, 2010, 30 (13) :4590-4600
[5]
BRORSON JR, 1994, J NEUROSCI, V14, P187
[6]
Taurine protects transformed rat retinal ganglion cells from hypoxia-induced apoptosis by preventing mitochondrial dysfunction [J].
Chen, Ka ;
Zhang, Qianyong ;
Wang, Jian ;
Liu, Fengjin ;
Mi, Mantian ;
Xu, Hongxia ;
Chen, Fang ;
Zeng, Kaihong .
BRAIN RESEARCH, 2009, 1279 :131-138
[7]
Differential Roles of NMDA Receptor Subtypes in Ischemic Neuronal Cell Death and Ischemic Tolerance [J].
Chen, Min ;
Lu, Ting-Jia ;
Chen, Xiao-Jing ;
Zhou, Yang ;
Chen, Qian ;
Feng, Xiao-Yan ;
Xu, Li ;
Duan, Wen-Hu ;
Xiong, Zhi-Qi .
STROKE, 2008, 39 (11) :3042-3048
[8]
GLUTAMATE NEUROTOXICITY AND DISEASES OF THE NERVOUS-SYSTEM [J].
CHOI, DW .
NEURON, 1988, 1 (08) :623-634
[9]
TARGETED DISRUPTION OF NMDA RECEPTOR-1 GENE ABOLISHES NMDA RESPONSE AND RESULTS IN NEONATAL DEATH [J].
FORREST, D ;
YUZAKI, M ;
SOARES, HD ;
NG, L ;
LUK, DC ;
SHENG, M ;
STEWART, CL ;
MORGAN, JI ;
CONNOR, JA ;
CURRAN, T .
NEURON, 1994, 13 (02) :325-338
[10]
DIRECT EVIDENCE THAT EXCITOTOXICITY IN CULTURED NEURONS IS MEDIATED VIA N-METHYL-D-ASPARTATE (NMDA) AS WELL AS NON-NMDA RECEPTORS [J].
FRANDSEN, A ;
DREJER, J ;
SCHOUSBOE, A .
JOURNAL OF NEUROCHEMISTRY, 1989, 53 (01) :297-299