Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways - PubMed

Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways

G E Hardingham et al. Nat Neurosci. 2002 May.

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.

Comment in

• What a privilege to reside at the synapse: NMDA receptor signaling to CREB.

  Riccio A, Ginty DD. Riccio A, et al. Nat Neurosci. 2002 May;5(5):389-90. doi: 10.1038/nn0502-389. Nat Neurosci. 2002. PMID: 11976696 No abstract available.

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