The DREAM protein negatively regulates the NMDA receptor through interaction with the NR1 subunit

Ying Zhang, Ping Su, Ping Liang, Tao Liu, Xu Liu, Xin Ying Liu, Bo Zhang, Tao Han, Yan Bing Zhu, Dongmin Yin, Junfa Li, Zhuan Zhou, Ke Wei Wang, Yun Wang

Research output: Contribution to journalArticle

55 Citations (Scopus)

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 on in vitro neuronal excitotoxic injury and in vivo ischemic 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.

Original languageEnglish (US)
Pages (from-to)7575-7586
Number of pages12
JournalJournal of Neuroscience
Volume30
Issue number22
DOIs
StatePublished - Jun 2 2010

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Kv Channel-Interacting Proteins
N-Methyl-D-Aspartate Receptors
Neuroprotective Agents
Proteins
Binding Sites
Wounds and Injuries
N-Methylaspartate
Neurodegenerative Diseases
Glutamic Acid
Epilepsy
Stroke
Clinical Trials
Neurons
Peptides

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The DREAM protein negatively regulates the NMDA receptor through interaction with the NR1 subunit. / Zhang, Ying; Su, Ping; Liang, Ping; Liu, Tao; Liu, Xu; Liu, Xin Ying; Zhang, Bo; Han, Tao; Zhu, Yan Bing; Yin, Dongmin; Li, Junfa; Zhou, Zhuan; Wang, Ke Wei; Wang, Yun.

In: Journal of Neuroscience, Vol. 30, No. 22, 02.06.2010, p. 7575-7586.

Research output: Contribution to journalArticle

Zhang, Y, Su, P, Liang, P, Liu, T, Liu, X, Liu, XY, Zhang, B, Han, T, Zhu, YB, Yin, D, Li, J, Zhou, Z, Wang, KW & Wang, Y 2010, 'The DREAM protein negatively regulates the NMDA receptor through interaction with the NR1 subunit', Journal of Neuroscience, vol. 30, no. 22, pp. 7575-7586. https://doi.org/10.1523/JNEUROSCI.1312-10.2010
Zhang, Ying ; Su, Ping ; Liang, Ping ; Liu, Tao ; Liu, Xu ; Liu, Xin Ying ; Zhang, Bo ; Han, Tao ; Zhu, Yan Bing ; Yin, Dongmin ; Li, Junfa ; Zhou, Zhuan ; Wang, Ke Wei ; Wang, Yun. / The DREAM protein negatively regulates the NMDA receptor through interaction with the NR1 subunit. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 22. pp. 7575-7586.
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AU - Zhang, Bo

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