The DREAM Protein Negatively Regulates the NMDA Receptor through Interaction with the NR1 Subunit
The DREAM Protein Negatively Regulates the NMDA Receptor through Interaction with the NR1 Subunit
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DREAM 蛋白通过与 NR1 亚基相互作用负向调节 NMDA 受体
DOI：
10.1523/jneurosci.1312-10.2010
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发表时间：
2010-06
影响因子：
5.3
通讯作者：
Zhu, Yan-Bing
中科院分区：
文献类型：
--
作者：
Zhang, Ying;Yin, Dong-Min;Li, Junfa;Zhou, Zhuan;Wang, Ke-Wei;Wang, Yun;Su, Ping;Liang, Ping;Liu, Tao;Liu, Xu;Liu, Xin-Ying;Zhang, Bo;Han, Tao;Zhu, Yan-Bing
谷氨酸诱导的兴奋性毒性与中风、癫痫和神经退行性疾病的病因有关。NMDA受体（NMDAR）在兴奋性毒性损伤中起关键作用;然而，测试NMDAR拮抗剂作为神经保护剂的临床试验一直令人沮丧。新型神经保护剂分子的开发正在积极进行。在这里，我们报告，下游调控元件拮抗剂调节剂（DREAM）显着抑制表面表达的NMDAR和NMDAR介导的电流。DREAM的过表达表现出对兴奋性毒性神经元损伤的神经保护作用，而DREAM的敲低增强NMDA诱导的毒性。DREAM可直接与NR 1亚基的C 0结构域结合。虽然DREAM含有NR 1亚基的多个结合位点，但N末端的残基21-40是NR 1亚基的主要结合位点。因此，21-40个残基可能通过竞争性机制解除由残基1-50赋予的自抑制并解除DREAM核心结构域的抑制。有趣的是，根据DREAM与NR 1亚基的关键结合位点构建的细胞渗透达特-21-40肽抑制原代培养的海马神经元中NMDAR介导的电流，并对体外神经元兴奋性毒性损伤和体内缺血性脑损伤具有神经保护作用。此外，达特-21-40的预处理和后处理均有效对抗兴奋性毒性。总之，这项工作揭示了一种新的NMDARs负调控因子，并为治疗兴奋性毒性相关疾病提供了一种有吸引力的候选药物。
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.
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DOI：
10.1523/jneurosci.19-04-01165.1999
发表时间：
1999-02
期刊：
The Journal of Neuroscience
影响因子：
--
作者：
J. Krupp;B. Vissel;C. G. Thomas;S. Heinemann;G. Westbrook
通讯作者：
J. Krupp;B. Vissel;C. G. Thomas;S. Heinemann;G. Westbrook
影响因子：
3
作者：
Rodriguez, R;Santiago-Mejia, J;San-Juan, ER
通讯作者：
San-Juan, ER
影响因子：
3
作者：
Wexler, EJ;Peters, EE;Kerr, JS
通讯作者：
Kerr, JS
DOI：
--
发表时间：
2003
期刊：
--
影响因子：
--
作者：
C. Lilliehook;O. Bozdagi;Jun Yao;M. Gomez-Ramirez;N. F. Zaidi;W. Wasco;S. Gandy;A. Santucci;V. Haroutunian;G. W. Huntley;J. Buxbaum
通讯作者：
C. Lilliehook;O. Bozdagi;Jun Yao;M. Gomez-Ramirez;N. F. Zaidi;W. Wasco;S. Gandy;A. Santucci;V. Haroutunian;G. W. Huntley;J. Buxbaum
影响因子：
4.8
作者：
Lin, L;Jeanclos, EM;Anand, R
通讯作者：
Anand, R