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The DREAM Protein Negatively Regulates the NMDA Receptor through Interaction with the NR1 Subunit
- 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.
- Subjects :
- Patch-Clamp Techniques
Time Factors
Xenopus
Excitotoxicity
Brain Edema
Cell Count
Hippocampal formation
medicine.disease_cause
Hippocampus
Brain Ischemia
Membrane Potentials
Mice
Cricetinae
Excitatory Amino Acid Agonists
RNA, Small Interfering
Hypoxia
Cells, Cultured
Neurons
Mice, Inbred BALB C
Gene knockdown
musculoskeletal, neural, and ocular physiology
General Neuroscience
Kv Channel-Interacting Proteins
Articles
Protein Transport
Neuroprotective Agents
NMDA receptor
psychological phenomena and processes
Protein Binding
Brain Infarction
N-Methylaspartate
Green Fluorescent Proteins
CHO Cells
Biology
Transfection
Receptors, N-Methyl-D-Aspartate
Neuroprotection
Cricetulus
In vivo
medicine
Animals
Humans
Immunoprecipitation
Biotinylation
Binding site
Analysis of Variance
Dose-Response Relationship, Drug
L-Lactate Dehydrogenase
Antagonist
Embryo, Mammalian
Rats
Repressor Proteins
Disease Models, Animal
Glucose
Gene Expression Regulation
nervous system
Mutation
Oocytes
Peptides
Neuroscience
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....c6307b40a249f74ceef399c1bf72cc3a