PMID- 23839940
OWN - NLM
STAT- MEDLINE
DCOM- 20131126
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 33
DP  - 2013 Aug 16
TI  - Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic 
      N-methyl-D-aspartate receptor function and neuronal excitotoxicity.
PG  - 24151-9
LID - 10.1074/jbc.M113.482000 [doi]
AB  - 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.
FAU - Zhou, Xianju
AU  - Zhou X
AD  - Department of Physiology, Michigan State University, East Lansing, Michigan 
      48824, USA.
FAU - Ding, Qi
AU  - Ding Q
FAU - Chen, Zhuoyou
AU  - Chen Z
FAU - Yun, Huifang
AU  - Yun H
FAU - Wang, Hongbing
AU  - Wang H
LA  - eng
GR  - R01 MH093445/MH/NIMH NIH HHS/United States
GR  - R03 NS072668/NS/NINDS NIH HHS/United States
GR  - MH093445/MH/NIMH NIH HHS/United States
GR  - NS072668/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130709
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (Neurotoxins)
RN  - 0 (Protein Subunits)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - IY9XDZ35W2 (Glucose)
RN  - S88TT14065 (Oxygen)
RN  - VH92ICR8HX (N-methyl D-aspartate receptor subtype 2A)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cell Death/drug effects
MH  - Cell Hypoxia/drug effects
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Gene Knockdown Techniques
MH  - Glucose/deficiency
MH  - Intracellular Space/drug effects/metabolism
MH  - Neurons/drug effects/metabolism/*pathology
MH  - Neurotoxins/*toxicity
MH  - Oxygen/pharmacology
MH  - Protein Subunits/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Signal Transduction/drug effects
MH  - Synapses/drug effects/*metabolism
PMC - PMC3745357
OTO - NOTNLM
OT  - CREB
OT  - Calcium Signaling
OT  - Cell Death
OT  - Excitotoxicity
OT  - Glutamate Receptors Ionotropic (AMPA, NMDA)
OT  - Neurodegeneration
OT  - Synapses
EDAT- 2013/07/11 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/08/16
CRDT- 2013/07/11 06:00
PHST- 2013/07/11 06:00 [entrez]
PHST- 2013/07/11 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/08/16 00:00 [pmc-release]
AID - S0021-9258(20)45301-3 [pii]
AID - M113.482000 [pii]
AID - 10.1074/jbc.M113.482000 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 Aug 16;288(33):24151-9. doi: 10.1074/jbc.M113.482000. Epub 2013 
      Jul 9.