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![Page 1: Glutamate Receptor Ion Channels: Structure, Regulation, and Function Department of Physiology, Shandong University School of Medicine ( Shu Yan Yu )](https://reader036.fdocuments.in/reader036/viewer/2022070411/56649f3e5503460f94c5e12b/html5/thumbnails/1.jpg)
Glutamate Receptor Ion
Channels: Structure,
Regulation, and Function
Department of Physiology, Shandong University
School of Medicine ( Shu Yan Yu)
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glutamate receptor (GluR) is the most important excitatory transmitter in the
CNS
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Ionotropic Glutamate Receptors
AMPA
NMDA
KA
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NMDA receptor:
NR1/NR2A; NR1/NR2B;
NR1/NR2A/2B
AMPA receptor:
GluR1/GluR2; GluR2/GluR3
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StructureIonotropic Glutamate
Receptors
AMPA-R NMDA-R
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Binding sites for agonists, antagonists, and modulators in the ligand binding domain(LBD), amino terminal domain (ATD), and transmembrane domain (TMD)
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Transmembrane topology (A) and crystal structure of the agonist-binding domain (B–D) of the GluA2 subunit protein
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GluA2 subunit protein
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GluA2 subunit protein
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P
P
P
P
Mg2+
Cytoplasmic
21 34
Glu
Cytoplasmic
PPP
K+
Na+
Ca2+
Zn2+ site
glycosylationsite
H+ sitePolyamine site
glycine coagonist site
redox site
S S
MK-801,PCP site
phosphorylation site
N
C
Scaffolding/Signalling Proteins
NR1 NR2
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Before Stimulation
During Stimulation
After Stimulation
Mg2+ block relieved_ _ _ _ _ _
+ ++ + +++ ++ + ++
_ _ _ _ _ _
Neuron A Neuron A Neuron A
Neuron B Neuron B Neuron B
NMDA receptor
blocked by Mg2+
Glutamate locks into receptor
Ca2+ flows throughNMDA receptor
Ca2+
Glutamate
Glutamate release / Depolarization
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NR2 subunit determines the functional properties of
NMDAR
Monyer et al. (1994), Neuron, 12, 529-540
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Inh
ibit
ion
of
NM
DA
R-E
PS
C (
%)
NVP-
AAM077 Ro25-
6981 Ro25-
6981 NVP-
AAM077
NVP first Ro first
0
20
40
60
80
100NVP-AAM077Ro25-6981
C100 ms
50 pA
25
pA
1
2
3
100 ms25 pA
25
pA
1
2
3
A B
Yu et al. Neuroscience. 2010
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Monyer et al. 2012
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Function
Role in Synaptic Function and Plasticity
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Two important types of synaptic plasticity :
Long-term potentiation (LTP ) ;
Long-term depression (LTD ) ;
They are two potential mechanism that underlie
learning and memory
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Bidirectional synaptic plasticity in the hippocampus
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Amygdala
SAH et al. Physiol Rev. Vol 83. P813
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Fear conditioning
一朝被蛇咬,十年怕井绳
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1. The method for recording:
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Whole-cell Patch RecordingAdvantage: . Single cell recording. Record currents through multiple channels at once. Can do both current clamp and voltage clamp. lower access resistance & easier to clamp. Bigger response . Easy to apply compound intracellularly & modify intracellular component & pathway . Using membrane impermeable drug can distinguish post/pre-synaptic effect
Disadvantage: . Dilute cytoplasmic components ("dialyzing“ the cell's contents) . Hard to get stable & long last recording
There is a "grace period" at the beginning of a whole-cell recording, lasting approximately 10 minutes, when one can take measurements before the cell has been dialyzed.
Action Potential/current, EPSP/EPSC, IPSP/IPSC
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Cuts ultra-thin (100-400 µm) brain slices for electrophysiological and imaging studies.
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Cleaning procedure Patch procedure
Visualized Patch
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1. Approaching 2. Attaching 3. Seal formation 4. Rupture of membrane
A small repetitive current or voltage pulse is applied to the electrode at relatively high frequency (e.g., 10 Hz) and the voltage or current response is monitored with anoscilloscope
Blind Patch
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whole cell patch clamp recording
were used to record evoked
EPSC/IPSC or EPSP/IPSP in coronal
slice.
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E(I)PSP vs E(I)PSC
EPSP ------ Excitatory Post Synaptic Potential
IPSP ------ Inhibitory Post Synaptic Potential
Measured By Current Clamp
Measured By Voltage Clamp
0.5
mV
50 ms
EPSC ------ Excitatory Post Synaptic Current
IPSC ------ Inhibitory Post Synaptic Current
10
0p
A
50ms
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(一)Role of NMDA Receptors in LTP/LTD induction
2. Results:
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HFS induction of LTP is NMDAR-dependent, APV (NMDA-R antagonist) blocked the induction of LTP
Control APV
40 mS
10
0 p
A
40 mS
10
0 p
A
1
2
1
2
ControlAPV
-10 0 10 20 30 40 50 60
Time (min)
0.6
1.0
1.4
1.8
2.2
Nor
mal
ized
EP
SC
Am
plitu
de
ControlAPVControlAPV
-10 0 10 20 30 40 50 60
Time (min)
0.6
1.0
1.4
1.8
2.2
Nor
mal
ized
EP
SC
Am
plitu
de
HFS
1 2
Yu et al. Journal of Neurochemistry. 2008
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APV blocked the induction of LTD by Pairing
protocol Control APV
40 mS
10
0 pA
40 mS
10
0 pA
1
2
1
2
-10 0 10 20 30 40 50 600.2
0.4
0.6
0.8
1.0
1.2
ControlAPVControlAPV
Time (min)
Nor
mal
ized
EP
SC
Am
plitu
de
Pairing
12
Yu et al. Journal of Neurochemistry. 2008
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Why one receptor leads to
two Bidirectional synaptic
plasticity ---
LTP and LTD ?
Many Hypothesis
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NR2 subunit determines the functional properties of
NMDAR
Monyer et al. (1994), Neuron, 12, 529-540
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NR2A antagonist NVP block the induction of LTP
00.2
0.40.6
0.81
1.21.41.61.8
2
0 10 20 30 40 50 60Time (min)
EP
SC
Am
plit
ude
(100
%)
NVP 0.4 uMControl
NVP-AAM077 (0.4uM, NVP: NR2A antagonist ) block the induction of LTP.
Dalton et al. Neuropharmacology 2012
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NR2B antagonist Ro25-6981 can’t block the induction of LTP
Time (min)
EP
SC
Am
plitu
de (
100%
)
R o25-6981 3uM
C ontro lR o25-6981 0 .5uM
Dalton et al. Neuropharmacology 2012
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NR2A antagonist NVP can’t block the induction of LTD
Dalton et al. Neuropharmacology 2012
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NR2A/2B antagonist as a pharmacological tool to
investigate the physiological role of LTP/LTD
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(二)Role of AMPA Receptors in LTP/LTD induction
NMDA-RAMPA-R
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Glu
AMPA NMDA20 ms
NMDA
AMPA
20pA
NMDA
AMPA
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Long-TermPotentiation
control
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Bidirectional synaptic plasticity in the hippocampus
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AMPA receptors
NMDA receptors
AMPA receptor-containingsecretory vesicles
AMPA receptor-containingclathrin-coated vesicles
?
Degradation?Synthesis
Pre-synaptic terminal
Post-synaptic neuron
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Bidirectional hippocampal synaptic plasticity
Hypothesis:
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A
-10 0 10 20 30 40 50 60
0.6
1.0
1.4
1.8
2.2
ControlTeTxControlTeTx
No
rma
lize
d E
PS
C A
mp
litud
e
Time (min)
Control TeTx
40 mS
10
0 p
A
40 mS
10
0 p
A
Pairing
1
2
1
2
1 2
TeTx prevent the expression of LTP in LA
Yu et al. Journal of Neurochemistry. 2008
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Control GluR2-3YControl GluR2-3Y
-10 0 10 20 30 40 50 600.2
0.4
0.6
0.8
1.0
1.2
ControlGluR2-3Y
No
rma
lize
d E
PS
C A
mp
litud
e
Time (min)
-10 0 10 20 30 40 50 600.2
0.4
0.6
0.8
1.0
1.2
ControlGluR2-3YControlGluR2-3Y
No
rma
lize
d E
PS
C A
mp
litud
e
Time (min)
Pairing
1
2
1
2
12
GluR2-3Y prevent the LTD
expression in LA
Yu et al. Journal of Neurochemistry. 2008
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Increased expression of AMPA receptors in membrane surface of LA neurons during the induction of LTP
0.00.20.40.60.81.01.21.41.6
Nor
mal
ized
Sur
face
Exp
ress
ion *
*
Yu et al. Journal of Neurochemistry. 2008
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Possible Signal Cascade Involved in the Expression of LTP and LTD
PSD-95SynGAP
CaMKII
Ras-GDP
Ras-GTP
Ca2+
Ca2+
Ca 2+
Ca 2+
Ca2+
Ca2+
Ca2+
Ca2
+
MEKRasGRF2
ERK1/2P
LTP
Ras
GR
F1
CREB
P
PI3K
AKT LTDp38
Cell DeathCell Survival
Mitochondria
VGCC
AMPAR
NR1/NR2ANR1/NR2A/NR2B
NR1/NR2B
AMPAR
P
Rap
-GD
P
Rap
-GT
P
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(Stress)Behaviour
Synaptic Plasticity(LTP/LTD)
Learning Memoryoutput
Behaviour Results
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The forced swim test
The forced swim test is a predictive model
widely used for assessing antidepressant
efficacy.
The immobility time of animals in the cylinder is
interpreted as representing despair or a
depression-like state which can be shortened by
repeated antidepressant treatment.
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Imm
obil
ity
tim
e (s
)
0
50
100
150
200
****
##
**
Vehicle
Curcumin
Fluoxetine
CCP
+ + +
++
+
+ + +
+
+--
-
--
- -
--
- -
--
Yu et al. Prog Neuropsychopharmacol Biol Psychiatry. 2013
Pre-treatment with CPP (a competitive NMDA receptor antagonist)
decreased anti-depressant effects of curcumin and fluoxetine.
![Page 59: Glutamate Receptor Ion Channels: Structure, Regulation, and Function Department of Physiology, Shandong University School of Medicine ( Shu Yan Yu )](https://reader036.fdocuments.in/reader036/viewer/2022070411/56649f3e5503460f94c5e12b/html5/thumbnails/59.jpg)
Imm
obili
ty t
ime
(s)
0
50
100
150
200
** **
Vehicle
Curcumin
NVP-AAM077
+ +
+
+
+ +
+
-
-
--
-
Yu et al. Prog Neuropsychopharmacol Biol Psychiatry. 2013
Pre-treatment with NVP-AAM077 (a GluN2A-prefering antagonist) can’t
prevent the anti-depressant effects of curcumin.
![Page 60: Glutamate Receptor Ion Channels: Structure, Regulation, and Function Department of Physiology, Shandong University School of Medicine ( Shu Yan Yu )](https://reader036.fdocuments.in/reader036/viewer/2022070411/56649f3e5503460f94c5e12b/html5/thumbnails/60.jpg)
Imm
obil
ity
tim
e (s
)
0
50
100
150
200
**
##
Vehicle
Curcumin
Ro25-6981
+ +
+
+
+ +
+
-
-
--
-
Yu et al. Prog Neuropsychopharmacol Biol Psychiatry. 2013
Pre-treatment with Ro25-6981 (a specific GluN2B antagonist) prevent
the anti-depressant effects of curcumin.
![Page 61: Glutamate Receptor Ion Channels: Structure, Regulation, and Function Department of Physiology, Shandong University School of Medicine ( Shu Yan Yu )](https://reader036.fdocuments.in/reader036/viewer/2022070411/56649f3e5503460f94c5e12b/html5/thumbnails/61.jpg)