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The DREAM protein negatively regulates the NMDA receptor through interaction with the NR1 subunit.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2010 Jun 02; Vol. 30 (22), pp. 7575-86. - Publication Year :
- 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 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.
- Subjects :
- Analysis of Variance
Animals
Biotinylation methods
Brain Edema etiology
Brain Edema metabolism
Brain Infarction etiology
Brain Infarction metabolism
Brain Ischemia complications
Brain Ischemia drug therapy
Brain Ischemia metabolism
CHO Cells
Cell Count methods
Cells, Cultured
Cricetinae
Cricetulus
Disease Models, Animal
Dose-Response Relationship, Drug
Embryo, Mammalian
Excitatory Amino Acid Agonists pharmacology
Gene Expression Regulation drug effects
Glucose deficiency
Green Fluorescent Proteins genetics
Hippocampus cytology
Humans
Hypoxia
Immunoprecipitation
Kv Channel-Interacting Proteins genetics
L-Lactate Dehydrogenase metabolism
Membrane Potentials drug effects
Membrane Potentials genetics
Mice
Mice, Inbred BALB C
Mutation physiology
N-Methylaspartate pharmacology
Neurons drug effects
Neurons physiology
Neuroprotective Agents metabolism
Neuroprotective Agents pharmacology
Oocytes
Patch-Clamp Techniques methods
Peptides genetics
Peptides therapeutic use
Protein Binding drug effects
Protein Binding genetics
Protein Transport drug effects
Protein Transport genetics
RNA, Small Interfering pharmacology
Rats
Receptors, N-Methyl-D-Aspartate genetics
Repressor Proteins genetics
Time Factors
Transfection methods
Xenopus
Gene Expression Regulation physiology
Kv Channel-Interacting Proteins physiology
Receptors, N-Methyl-D-Aspartate metabolism
Repressor Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 30
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 20519532
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.1312-10.2010