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DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke
- Source :
- Cell. 140(2):222-234
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
Abstract
- SummaryN-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extrasynaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292-1304 (NR2BCT). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2BCT that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca2+ influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extrasynaptic sites and this interaction acts as a central mediator for stroke damage.
- Subjects :
- AMPA receptor
Receptors, N-Methyl-D-Aspartate
MOLNEURO
General Biochemistry, Genetics and Molecular Biology
Brain Ischemia
Brain ischemia
Mice
Enzyme-linked receptor
medicine
Animals
Receptor
Protein kinase A
Neurons
biology
Cell Death
Biochemistry, Genetics and Molecular Biology(all)
musculoskeletal, neural, and ocular physiology
Glutamate receptor
Brain
medicine.disease
Recombinant Proteins
Cell biology
Stroke
Death-Associated Protein Kinases
nervous system
Biochemistry
Calcium-Calmodulin-Dependent Protein Kinases
biology.protein
GRIN2A
NMDA receptor
tat Gene Products, Human Immunodeficiency Virus
Apoptosis Regulatory Proteins
Peptides
psychological phenomena and processes
Subjects
Details
- ISSN :
- 00928674
- Volume :
- 140
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cell
- Accession number :
- edsair.doi.dedup.....620d9a77df19ed01e25dbb83c8b76c06
- Full Text :
- https://doi.org/10.1016/j.cell.2009.12.055