Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Brain-Derived Neurotrophic Factor / genetics
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Brain-Derived Neurotrophic Factor / metabolism
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Calcium / metabolism
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Calcium Channels, L-Type / metabolism
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Calcium Signaling / drug effects
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Cell Death / drug effects
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Cell Death / physiology
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Cell Hypoxia / physiology
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Glutamic Acid / pharmacology
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Intracellular Membranes / physiology
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Membrane Potentials / physiology
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Mitochondria / physiology
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Piperidines / pharmacology
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RNA, Messenger / metabolism
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Synapses / metabolism*
Substances
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Brain-Derived Neurotrophic Factor
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Calcium Channels, L-Type
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Cyclic AMP Response Element-Binding Protein
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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NR2B NMDA receptor
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Piperidines
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RNA, Messenger
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Receptors, N-Methyl-D-Aspartate
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Glutamic Acid
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ifenprodil
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Calcium