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The DREAM Protein Negatively Regulates the NMDA Receptor through Interaction with the NR1 Subunit

Authors :
Ping Su
Ying Zhang
Liu Tao
Ping Liang
Zhuan Zhou
Xu Liu
Bo Zhang
Yan Bing Zhu
Dong Min Yin
Xin Ying Liu
KeWei Wang
Yun Wang
Junfa Li
Tao Han
Source :
The Journal of Neuroscience. 30:7575-7586
Publication Year :
2010
Publisher :
Society for Neuroscience, 2010.

Abstract

Glutamate-induced excitotoxicity has been implicated in the etiology of stroke, epilepsy, and neurodegenerative diseases. NMDA receptors (NMDARs) play a pivotal role in excitotoxic injury; however, clinical trials testing NMDAR antagonists as neuroprotectants have been discouraging. The development of novel neuroprotectant molecules is being vigorously pursued. Here, we report that downstream regulatory element antagonist modulator (DREAM) significantly inhibits surface expression of NMDARs and NMDAR-mediated current. Overexpression of DREAM showed neuroprotection against excitotoxic neuronal injury, whereas knockdown of DREAM enhanced NMDA-induced toxicity. DREAM could directly bind to the C0 domain of the NR1 subunit. Although DREAM contains multiple binding sites for the NR1 subunit, residues 21-40 of the N terminus are the main binding site for the NR1 subunit. Thus, 21-40 residues might relieve the autoinhibition conferred by residues 1-50 and derepress the DREAM core domain by a competitive mechanism. Intriguingly, the cell-permeable TAT-21-40 peptide, constructed according to the critical binding site of DREAM to the NR1 subunit, inhibits NMDAR-mediated currents in primary cultured hippocampal neurons and has a neuroprotective effect onin vitroneuronal excitotoxic injury andin vivoischemic brain damage. Moreover, both pretreatment and posttreatment of TAT-21-40 is effective against excitotoxicity. In summary, this work reveals a novel, negative regulator of NMDARs and provides an attractive candidate for the treatment of excitotoxicity-related disease.

Details

ISSN :
15292401 and 02706474
Volume :
30
Database :
OpenAIRE
Journal :
The Journal of Neuroscience
Accession number :
edsair.doi.dedup.....c6307b40a249f74ceef399c1bf72cc3a