DAPK1与NMDA 受体NR2B亚单位相互作用介导卒中过程的脑损伤.pptVIP

-2 Welcome LIU Shiying Department of Neurology, Jiangxi Provincial People’s Hospital DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke Weihong Tu, Xin Xu, Lisheng Peng, et al. Department of Neurology and Neuroscience Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA Contents Summary 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. Summary 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. Summary 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. Summary 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. Summary 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. Results Figure 1. Ischemia Recruits DAPK1 into NMDA Receptor Complex Figure 2. The Mutant Mice Lacking the DAPK1 Geneshows the β-geo protein Figure 3. Activation of DAPK1 Induces Ca2+ Influx through Extrasynaptic NMDA Receptors Figure 4. Genetic Deletion of DAPK1 Protects against Ischemic Neuronal Death Figure 4. Genetic Deletion of DAPK1 Protects against Ischemic Neuronal Death Figure 4. Genetic Deletion of DAPK1 Protects against Ischemic Neuronal Death Figure 5. Inhibition of DAPK1-NMDA Receptor Interact