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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
[1]Robbins BASIC PATHOLOGY, 9th Edition
ischemia
hemorrhage
Keys
 DAPK1: Death-associated
Protein Kinase 1
死亡相关蛋白激酶1
 NMDAR: N-methyl-Daspartate 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
channel conductance
Figure 3. Robbins BASIC PATHOLOGY, 9th Edition
increased the NR1/NR2B Ca2+
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
A
Cortex B
Cortex
100μm
100μm
Striatum
Striatum
100μm
100μm
CA1
CA1
 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 FluoroJade (FJ), a marker for
degenerating neurons
Genetic deletion of DAPK1 protects
neurons against Ischemic injury.
100μm
100μm
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