DEATH-ASSOCIATED PROTEIN KINASE 1 REGULATION OF N-METHYL-D-ASPARTATE RECEPTOR IN STROKE
Document Type
Presentation
Start Date
22-10-2010 10:45 AM
End Date
22-10-2010 12:00 PM
Description
NMDA receptors constitute the major subtype of glutamate receptors and participate in rapid excitatory synaptic transmission throughout the central nervous system. Excessive stimulation of NMDA is considered to be the main factor responsible for brain damage in stroke. However, the essential physiological action of these receptors in synaptic transmission means that blocking them totally is not a feasible therapeutic option. An idea approach for the treatment of stroke should inhibit the specific NMDA receptor "cell death signals", whereby the pathological effects of the receptors is selectively blocked, leaving the physiological action unaffected. Recently, we have found that cerebral ischemia recruits death-associated protein kinase (DAPK1) into the NMDA receptor NR2B protein complex at extra-synaptic site. DAPK1 is a Ca2+/calmodulin (CaM)regulated serine/threonine kinase that mediates cell death. DAPK1 directly binds with NMDA receptor NR2B C-terminal tail consisting of amino acid 1292-1304 (NR2Bcr). Also whole-cell patch clamp recordings have demonstrated that constitutive activation of DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn increases the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 doesn't affect NMDA receptors synaptic transmission, and dramatically reduces brain infarction following ischemia. Thus, we conclude that DAPK1 physically and functionally interacts with NMDA receptor NR2B subunit at extra-synaptic sites and this interaction acts as a central mediator in stroke damage.
Recommended Citation
Xu, Xin; Tu, W.; Peng, L.; and Zhong, X., "DEATH-ASSOCIATED PROTEIN KINASE 1 REGULATION OF N-METHYL-D-ASPARTATE RECEPTOR IN STROKE" (2010). Dr. Joseph M. Moerschbaecher, III Graduate Research Day. 25.
https://digitalscholar.lsuhsc.edu/grad_rs/2010/poster1/25
DEATH-ASSOCIATED PROTEIN KINASE 1 REGULATION OF N-METHYL-D-ASPARTATE RECEPTOR IN STROKE
NMDA receptors constitute the major subtype of glutamate receptors and participate in rapid excitatory synaptic transmission throughout the central nervous system. Excessive stimulation of NMDA is considered to be the main factor responsible for brain damage in stroke. However, the essential physiological action of these receptors in synaptic transmission means that blocking them totally is not a feasible therapeutic option. An idea approach for the treatment of stroke should inhibit the specific NMDA receptor "cell death signals", whereby the pathological effects of the receptors is selectively blocked, leaving the physiological action unaffected. Recently, we have found that cerebral ischemia recruits death-associated protein kinase (DAPK1) into the NMDA receptor NR2B protein complex at extra-synaptic site. DAPK1 is a Ca2+/calmodulin (CaM)regulated serine/threonine kinase that mediates cell death. DAPK1 directly binds with NMDA receptor NR2B C-terminal tail consisting of amino acid 1292-1304 (NR2Bcr). Also whole-cell patch clamp recordings have demonstrated that constitutive activation of DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn increases the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 doesn't affect NMDA receptors synaptic transmission, and dramatically reduces brain infarction following ischemia. Thus, we conclude that DAPK1 physically and functionally interacts with NMDA receptor NR2B subunit at extra-synaptic sites and this interaction acts as a central mediator in stroke damage.