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PMID:20141836

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Citation

Tu, W, Xu, X, Peng, L, Zhong, X, Zhang, W, Soundarapandian, MM, Balel, C, Wang, M, Jia, N, Zhang, W, Lew, F, Chan, SL, Chen, Y and Lu, Y (2010) DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 140:222-34

Abstract

N-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 (NR2B(CT)). 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 NR2B(CT) that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca(2+) 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.

Links

PubMed PMC2820131 Online version:10.1016/j.cell.2009.12.055

Keywords

Animals; Apoptosis Regulatory Proteins/antagonists & inhibitors; Apoptosis Regulatory Proteins/genetics; Apoptosis Regulatory Proteins/metabolism; Brain/metabolism; Brain/pathology; Brain Ischemia/drug therapy; Brain Ischemia/metabolism; Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases/genetics; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Cell Death; Mice; Neurons/cytology; Neurons/metabolism; Peptides/metabolism; Receptors, N-Methyl-D-Aspartate/metabolism; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Stroke/drug therapy; Stroke/metabolism; Stroke/pathology; tat Gene Products, Human Immunodeficiency Virus/genetics; tat Gene Products, Human Immunodeficiency Virus/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:KCC2A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q01097

F

Seeded From UniProt

complete

MOUSE:NMDZ1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q01097

F

Seeded From UniProt

complete

MOUSE:NMDE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P11798

F

Seeded From UniProt

complete

MOUSE:NMDE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35438

F

Seeded From UniProt

complete

MOUSE:NMDE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q62108

F

Seeded From UniProt

complete

MOUSE:NMDE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q80YE7

F

Seeded From UniProt

complete

MOUSE:DLG4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q01097

F

Seeded From UniProt

complete

MOUSE:DAPK1

involved_in

GO:2000310: regulation of NMDA receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DAPK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q01097

F

Seeded From UniProt

complete


See also

References

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