PMID- 11953750
OWN - NLM
STAT- MEDLINE
DCOM- 20020513
LR  - 20220309
IS  - 1097-6256 (Print)
IS  - 1097-6256 (Linking)
VI  - 5
IP  - 5
DP  - 2002 May
TI  - Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell 
      death pathways.
PG  - 405-14
AB  - Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) 
      receptors have opposite effects on CREB (cAMP response element binding protein) 
      function, gene regulation and neuron survival. Calcium entry through synaptic 
      NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) 
      gene expression as strongly as did stimulation of L-type calcium channels. In 
      contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath 
      glutamate exposure or hypoxic/ischemic conditions, activated a general and 
      dominant CREB shut-off pathway that blocked induction of BDNF expression. 
      Synaptic NMDA receptors have anti-apoptotic activity, whereas stimulation of 
      extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an 
      early marker for glutamate-induced neuronal damage) and cell death. Specific 
      blockade of extrasynaptic NMDA receptors may effectively prevent neuron loss 
      following stroke and other neuropathological conditions associated with glutamate 
      toxicity.
FAU - Hardingham, G E
AU  - Hardingham GE
AD  - MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
FAU - Fukunaga, Y
AU  - Fukunaga Y
FAU - Bading, H
AU  - Bading H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Nat Neurosci
JT  - Nature neuroscience
JID - 9809671
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Calcium Channels, L-Type)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (Piperidines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - R8OE3P6O5S (ifenprodil)
RN  - SY7Q814VUP (Calcium)
SB  - IM
CIN - Nat Neurosci. 2002 May;5(5):389-90. PMID: 11976696
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism
MH  - Calcium/metabolism
MH  - Calcium Channels, L-Type/metabolism
MH  - Calcium Signaling/drug effects
MH  - Cell Death/drug effects/physiology
MH  - Cell Hypoxia/physiology
MH  - Cell Survival/drug effects/physiology
MH  - Cells, Cultured
MH  - Cyclic AMP Response Element-Binding Protein/antagonists & inhibitors/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Excitatory Amino Acid Antagonists/pharmacology
MH  - Gene Expression Regulation/drug effects/physiology
MH  - Glutamic Acid/pharmacology
MH  - Intracellular Membranes/physiology
MH  - Membrane Potentials/physiology
MH  - Mitochondria/physiology
MH  - Neurons/cytology/drug effects/*metabolism
MH  - Piperidines/pharmacology
MH  - RNA, Messenger/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/*metabolism
MH  - Signal Transduction/drug effects/*physiology
MH  - Synapses/*metabolism
EDAT- 2002/04/16 10:00
MHDA- 2002/05/15 10:01
CRDT- 2002/04/16 10:00
PHST- 2001/11/26 00:00 [received]
PHST- 2002/03/13 00:00 [accepted]
PHST- 2002/04/16 10:00 [pubmed]
PHST- 2002/05/15 10:01 [medline]
PHST- 2002/04/16 10:00 [entrez]
AID - nn835 [pii]
AID - 10.1038/nn835 [doi]
PST - ppublish
SO  - Nat Neurosci. 2002 May;5(5):405-14. doi: 10.1038/nn835.