The DREAM protein negatively regulates the NMDA receptor through interaction with the NR1 subunit.
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.
Zhang
Ying
Y
Neuroscience Research Institute, Key Laboratory for Neuroscience of Ministry of Education and Health, Peking University, Beijing, China.
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
D000704:Analysis of Variance; D000818:Animals; D019921:Biotinylation / Q000379:methods; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism; D020520:Brain Infarction / Q000209:etiology / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D016466:CHO Cells; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D000860:Hypoxia; D047468:Immunoprecipitation; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D010455:Peptides / Q000235:genetics / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014981:Xenopus
D018690:Excitatory Amino Acid Agonists; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; C409466:NR1 NMDA receptor; D018696:Neuroprotective Agents; D010455:Peptides; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate; D007770:L-Lactate Dehydrogenase; D005947:Glucose