Editors' ChoiceNeurobiology

NMDA Receptors Sensitize Cells to Acidic Conditions

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Science's STKE  06 Dec 2005:
Vol. 2005, Issue 313, pp. tw434
DOI: 10.1126/stke.3132005tw434

Certain neurons, such as hippocampal CA1 neurons, are highly susceptible to ischemic cell death, which is caused by reduced blood flow leading to cellular acidification and decreased oxygen and glucose delivery. Both N-methyl-D-aspartate (NMDA) type glutamate receptors and acid-sensing ion channels (ASICs) have been implicated in ischemic cell death, and now Gao et al. uncover a signaling pathway connecting these to calcium-conducting channels. Four-vessel occlusion of rats to produce global brain ischemia resulted in the increased abundance of ASIC1a (3 to 6 hours following transient ischemia) and increased phosphorylation of ASIC1a (5 to 30 minutes of ischemia) in the hippocampus. Ischemia-induced phosphorylation of ASIC1a was blocked by calcium/calmodulin-dependent protein kinase II (CaMKII) inhibition or NMDA inhibition or a more selective inhibitor for NMDA receptors containing the NR2B subunit, which is known to bind and recruit CaMKII to the postsynaptic density. The CaMKII phosphorylation site on ASIC1a was mapped to two nonconserved serines in the C terminus of the channel, thus explaining the selective participation of this isoform of ASICs in acid-induced neuronal toxicity. Transfection of mutants that could not be phosphorylated by CaMKII was neuroprotective for cells exposed to ischemia and low pH. In cultured neurons or transfected cells, either activation of NMDA-NR2B receptors or ischemia increased ASIC currents evoked by subsequent exposure to acidic conditions. In hippocampal neurons, inhibitors of CaMKII or NMDA-NR2B receptors blocked the increase in ASIC currents. Reduction of expression of ASIC1a with short interfering RNA (siRNA) reduced hippocampal neuron death induced by acid conditions. Pharmacological inhibition of either NMDA-NR2B or ASIC1a decreased cultured hippocampal cell death induced by combined acidic and ischemic conditions. Recruitment of CaMKII to the NR2B subunit of the NMDA receptor during ischemia allows CaMKII to phosphorylate ASIC1a. This phosphorylation sensitizes the channel to low pH, exacerbating cell death by allowing increased calcium conductance.

J. Gao, B. Duan, D-.G. Wang, X.-H. Deng, G.-Y. Zhang, L. Xu, T.-L. Xu, Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death. Neuron 48, 635-646 (2005). [PubMed]

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