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

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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6632380 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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

Zhang Ying Y Su Ping P Liang Ping P Liu Tao T Liu Xu X Liu Xin-Ying XY Zhang Bo B Han Tao T Zhu Yan-Bing YB Yin Dong-Min DM Li Junfa J Zhou Zhuan Z Wang Ke-Wei KW Wang Yun Y

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100601 22

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 ...[more]

PMID: 20519532

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Project description:BackgroundThe present study explored the serum glutamate (Glu), glutamine (Gln), glutamic acid dehydrogenase (GAD) concentrations and the mRNA expression levels of the N-methyl-D-aspartate receptor (NMDAR) NR1 subunit in the peripheral blood of patients with insomnia disorder (ID). To our knowledge, this is the first study showing an increase in the mRNA expression levels of the NMDAR NR1 subunit in patients with ID.MethodsThis study included 30 ID patients and 30 matched healthy controls. We investigated the demographic and illness information and assessed subjective sleep quality using the Pittsburgh Sleep Quality Index. The Hamilton Depression Scale-17 and Hamilton Anxiety Scale were used to evaluate the patients' symptoms of depression and anxiety, respectively. The quantifications of Glu, Gln and GAD concentrations were performed by Enzyme-linked immunosorbent assay (ELISA). Real-time PCR was used to detect the mRNA expression levels of the NMDAR NR1 subunit in peripheral blood.ResultsCompared with the healthy control group, the serum Glu concentrations and the mRNA expression levels of the NMDAR NR1 subunit in the ID group were significantly higher. However, there was no significant difference in Gln and GAD between the two groups. The receiver operating characteristic (ROC) analysis showed that the mRNA expression levels of the NMDAR NR1 subunit could distinguish ID patients from healthy individuals (area under the curve: 0.758; sensitivity: 73.3%; specificity: 76.7%). A negative correlation was found between the mRNA expression levels of the NMDAR NR1 subunit for age, total duration of illness, and age of first onset in the ID group, whereas a positive correlation was detected for daytime dysfunction.ConclusionGlutamatergic neurotransmission was abnormal in ID patients. Additionally, the mRNA expression levels of the NMDAR NR1 subunit appeared to have potential as a clinical biomarker for ID. However, the sample size of our study was limited, and future studies with larger sample sizes are needed to further validate and explore the mechanisms involved and to assess the reliability of the biomarker.

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

Publications

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

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