N-Methyl-d-aspartate receptor subunit- and neuronal-type dependence of excitotoxic signaling through post-synaptic density 95
Article first published online: 28 SEP 2010
© 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry
Journal of Neurochemistry
Special Issue: Introducing Preclinical Systematic Reviews
Volume 115, Issue 4, pages 1045–1056, November 2010
How to Cite
Fan, J., Vasuta, O. C., Zhang, L. Y. J., Wang, L., George, A. and Raymond, L. A. (2010), N-Methyl-d-aspartate receptor subunit- and neuronal-type dependence of excitotoxic signaling through post-synaptic density 95. Journal of Neurochemistry, 115: 1045–1056. doi: 10.1111/j.1471-4159.2010.06994.x
- Issue published online: 21 OCT 2010
- Article first published online: 28 SEP 2010
- Accepted manuscript online: 10 SEP 2010 06:42PM EST
- Received April 28, 2010; revised manuscript received August 16, 2010; accepted September 3, 2010.
- NMDA receptor;
J. Neurochem. (2010) 115, 1045–1056.
NMDA receptors (NMDARs) mediate excitatory synaptic transmission during repetitive or prolonged glutamate release, playing a critical role in synaptic plasticity or cell death, respectively. Evidence indicates that a major pathway of NMDAR signaling to cell death in cortical and hippocampal neurons requires the scaffolding protein post-synaptic density 95 (PSD-95) and activation of neuronal nitric oxide synthase. However, it is not known if this PSD-95-dependent pathway contributes to excitotoxicity in other brain regions. It is also unclear whether the neuroprotective effects of Tat-NR2B9c, a membrane-permeant peptide that disrupts PSD-95/NMDAR binding, correlate with uncoupling NR2B- and/or NR2A-type NMDARs from PSD-95. In this study, we used cultured hippocampal and striatal neurons to test the potency of Tat-NR2B9c on uncoupling NR2 subunits from PSD-95 and protecting against NMDA-induced excitotoxicity. We found that the concentration of Tat-NR2B9c required to dissociate 50% of PSD-95 was fourfold lower for NR2B than NR2A in cultured hippocampal and striatal neurons, and that this concentration correlated tightly with protection against NMDA-induced toxicity in hippocampal neurons without altering NMDAR current. In contrast, NMDAR signaling to cell death in cultured striatal neurons occurred independently of the NR2B/PSD-95 interaction or neuronal nitric oxide synthase activation. These results will facilitate development of neuronal type-specific protective therapies.