DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke

    Authors

    W. H. Tu; X. Xu; L. S. Peng; X. F. Zhong; W. F. Zhang; M. M. Soundarapandian; C. Balel; M. Q. Wang; N. L. Jia; W. Zhang; F. Lew; S. L. Chan; Y. F. Chen;Y. M. Lu

    Comments

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    Abbreviated Journal Title

    Cell

    Keywords

    PROTEIN-KINASE-II; CELL-DEATH; IN-VIVO; HIPPOCAMPAL-NEURONS; FOREBRAIN; ISCHEMIA; GLUTAMATE RELEASE; ION CHANNELS; ACTIVATION; NEURODEGENERATION; CALMODULIN; Biochemistry & Molecular Biology; Cell Biology

    Abstract

    N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extra-synaptic 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 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.

    Journal Title

    Cell

    Volume

    140

    Issue/Number

    2

    Publication Date

    1-1-2010

    Document Type

    Article

    Language

    English

    First Page

    222

    Last Page

    234

    WOS Identifier

    WOS:000273826500013

    ISSN

    0092-8674

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