DAPK1 Interaction with NMDA Receptor Mediates Brain Damage in Stroke 11307120230 杨佳柠 临床医学（八年制）
Stroke [1] acute cerebrovascular diseases brain disorders caused by pathologic processes involving blood vessels 3 main pathogenic mechanisms: thrombotic occlusion embolic occlusion vascular rupture ischemia hemorrhage [1]Robbins BASIC PATHOLOGY, 9th Edition
Keys DAPK1: Death-associated Protein Kinase 1 死亡相关蛋白激酶1 NMDAR: N-methyl-D- aspartate receptors N-甲基-D-天冬氨酸受体 Ischemic Brain Damage Figure 1. Pierre Paoletti and Jacques Neyton. NMDA receptor subunits: function and pharmacology, Current Opinion in Pharmacology, Vol. 7:39–47, 2007
Methods & Results Any changes after neurons suffering from ischemia? anti-NMDAR subunit NR2B antibodies focal cerebral ischemia: middle cerebral artery occlusion (MCAO) Ischemia recruits DAPK1 into NR2B complex. Figure 2. Youming Lu, et al. DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke, Cell, Vol.140(2):222-234, 2010
Methods & Results How does the DAPK1 interact with NR2B? generating a series of NMDA receptor NR2B C-terminal deletion mutants only the NR2B1292-1304 fragment capable of binding with DAPK1 (using a specific motif) coexpressing cDAPK1 with the normal NR1/NR2B or the mutant NR1/NR2B S1303 A receptors (a Ser-1303 residue replaced with an Ala) cDAPK1 increased the peak amplitude of the recombinant NR1/NR2B receptor currents, but not the mutant receptor
Methods & Results What happens after their interaction? coexpressing the NR1/NR2B receptors with a constitutively active DAPK1 (cDAPK1), or the wild-type DAPK1 (wDAPK1) DAPK1 activation increased the NR1/NR2B Ca2+ channel conductance Figure 3. Robbins BASIC PATHOLOGY, 9th Edition
Methods & Results Can neurons be protected if the interaction is inhibited? DAPK1-/- mutant mice Figure 4. Youming Lu, et al. DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke, Cell, Vol.140(2):222-234, 2010
Methods & Results Cortex 100μm Striatum CA1 A B treated the DAPK1-/- and DAPK1+/+ mice with transient global ischemia (occlusion of the common carotid artery for 20 min), then reperfusion 6 days after, stained with Fluoro- Jade (FJ), a marker for degenerating neurons Genetic deletion of DAPK1 protects neurons against Ischemic injury. Figure 5. Youming Lu, et al. DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke, Cell, Vol.140(2):222-234, 2010
Discussion DAPK1 only mediating neuron’s pathologic function, without affecting the normal physiologic function New targeting stroke therapy: DAPK1-NMDA receptor interaction DAPK1-specific inhibitors or antagonists Figure 6. Youming Lu, et al. DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke, Cell, Vol.140(2):222-234, 2010