DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke.
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.
Department of Neurology and Neuroscience Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA.
Weihong
W
Tu
Xin
X
Xu
Lisheng
L
Peng
Xiaofen
X
Zhong
Wenfeng
W
Zhang
Mangala M
MM
Soundarapandian
Cherine
C
Balel
Manqi
M
Wang
Nali
N
Jia
Wen
W
Zhang
Frank
F
Lew
Sic Lung
SL
Chan
Yanfang
Y
Chen
Youming
Y
Lu
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D064550:Death-Associated Protein Kinases; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C121001:NR2B NMDA receptor; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases