SRC UPREGULATION OF NMDA RECEPTORS: A COMMON LINK IN PAIN AND SCHIZOPHRENIA
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SRC UPREGULATION OF NMDA RECEPTORS: A COMMON LINK IN PAIN AND SCHIZOPHRENIA MICHAEL SALTER MD PHD FRSC U TORONTO CENTRE FOR THE STUDY OF PAIN
description
SRC UPREGULATION OF NMDA RECEPTORS: A COMMON LINK IN PAIN AND SCHIZOPHRENIA MICHAEL SALTER MD PHD FRSC U TORONTO CENTRE FOR THE STUDY OF PAIN. Na + Ca 2+. Na + Ca 2+. N. Gly. 4. 4. 3. 3. 1. 1. 2. 2. C. K +. Y P. Y P. K +. Y P. Y P. Y P. Phosphorylation - PowerPoint PPT Presentation
Transcript of SRC UPREGULATION OF NMDA RECEPTORS: A COMMON LINK IN PAIN AND SCHIZOPHRENIA
SRC UPREGULATION OF NMDA RECEPTORS:A COMMON LINK IN PAIN AND
SCHIZOPHRENIAMICHAEL SALTER MD PHD FRSC
U TORONTO CENTRE FOR THE STUDY OF PAIN
Mg2+
Cytoplasmic
2134
Glu
Cytoplasmic
K+
Na+
Ca2+
N
C
Scaffolding/Signalling Proteins
YP
YP
YP
YP
YP
Phosphorylation by Src kinase
21 3 4
Gly
N
C
K+
Na+
Ca2+
0.01
0.001
2 min0.1
0.01
2 min0.1
kinase activator
phosphatase
0.001
NMDA
phosphatase inhibitor
kinase inhibitor
Src upregulation of NMDA receptors Src upregulation of NMDA receptors in pathologic pain statesin pathologic pain states
Suppression of Src upregulation of Suppression of Src upregulation of NMDA receptors by neuregulin 1 – NMDA receptors by neuregulin 1 – ErbB4 signalingErbB4 signaling
Src upregulation of NMDA receptors Src upregulation of NMDA receptors in pathologic pain statesin pathologic pain states
Suppression of Src upregulation of Suppression of Src upregulation of NMDA receptors by neuregulin 1 – NMDA receptors by neuregulin 1 – ErbB4 signalingErbB4 signaling
NMDA receptor complex
ND2
SrcGingrich et al, PNAS 101: 6237-6242, 2004
NMDA receptor complex
SrcSrc 40-49
ND2
Tat Src40-49
Spinal cord
L5DRG
Sham
Nerve injury
0 1 2 3 40
5
10
15
20
50%
Th
resh
old (
g)
Time after surgery (weeks)
Experimental model of chronic constriction injury of a sensory nerve
Experimental models of chronic injury of a peripheral nerve
PNI-induced behaviours are reversed by Src40-49Tat
PNI-induced behaviours are reversed by Src40-49Tat
Src40-49Tat i.v. suppresses Src-ND2 association
PNI-induced increase in GluN2B tyrosine phosphorylation is reversed by Src40-49Tat
PNI-induced behaviours are suppressed Src-/- mice
Effect of Src40-49Tat is occluded in Src null mice
Liu et al. Nature Medicine 14:1325-1332, 2008
Src upregulation of NMDA receptors Src upregulation of NMDA receptors in pathologic pain statesin pathologic pain states
Suppression of Src upregulation of Suppression of Src upregulation of NMDA receptors by neuregulin 1 – NMDA receptors by neuregulin 1 – ErbB4 signalingErbB4 signaling
a
b
30 ms
10 mV
sSrc(40-58)
a
b Src (40-58)
Slope (
V/S
)
A
Slope (%
)
100
200
300a b
8
4
1
Ba
b
Anti-Src1
IgG
a
b
Slope (%
)
100
200
300a b
8
4
1
Slope (
V/S
)
Time (min)
0 20 40 60
fEP
SP
Slope (%
)
100
200
300
Time (min)
0 20 40 60
fEP
SP
slope (%)
100
200
300
Src (40-58)
sSrc(40-58)
Anti-Src1
IgG
2 mV2 m
V15 ms
15 ms
a
b
a
b
a b
a
b
a
b
a b
10 mV
Blocking Src Prevents LTP Induction in CA1
30 ms
Lu et al, Science 279: 1363, 199840 58
KPASADGHRGPSAAFVPPA
CAKb
STEP
NMDAR
Glu
AMPAR KAIR
Basal
Mg2+
Tetanus /Theta burst
Input
CAKb
Glu
Na+
P
CAKbP
Glu
Potentiated
Ca2+
ND2
SrcND2
SrcND2
Src
PTPαCsk
+--
GPCR, EphB and other signaling
P
AMPAR KAIR
Induction
Salter & Pitcher, 2011
ErbB Family of Receptors
Trends Cardiovasc Med 2:80-86, 2003
ErbB4 interacts with PSD-95 at excitatory synapses
Huang et al, Neuron 26:443-455, 2000
Ma et al, J. Neurosci. 23:3164 –3175, 2003
ErbB4 localizes in the PSD in spines
NRG1: 8p12-p21
ERBB4: 2p33.3-q34
Mei & Xiong Nature Rev Neuroci 9:437–452, 2008
b c
a
Time (min)
fEP
SP
slo
pe (
%)
0
25
50
75
100
125
APV
NRG
NBQX
Neuregulin
fEP
SP
slo
pe (
%)
fEP
SP
slo
pe (
%)
0 20 40 60 80
100
150
200
250
a b c
a b c
20 40 60 80Interval (ms)
0 250 500
Rat
io (
P2/
P1)
1.0
1.5
2.0
Time (min)
0 20 40 60 80
100
150
200
250
Control
Neuregulin
Time (min)
Huang et al, Neuron 26:443-455, 2000
Pitcher et al, NeuroReport 19:139-143, 2008
Pitcher et al, NeuroReport 19:139-143, 2008
Loss of function of ErbB4 enhances tbLTP in the hippocampal CA1
NRG1b prevents but does not reverse theta burst stimulation (TBS)-induced LTP in the hippocampal CA1
Pitcher et al, Nature Medicine 17:470-478, 2011
NRG1b has no effect on basal NMDAR EPSCs in CA1
Nor
mal
ized
NM
DA
EP
SC
A
mpl
itud
e (%
)Neuregulin Prevents Endogenous Src Activation-Dependent
Potentiation of Schaffer Collateral-Evoked NMDA Excitatory Postsynaptic Currents
NRG1b prevents endogenous Src activation-induced potentiation of NMDAR EPSCs in CA1
ErbB4 mediates NRG1b suppression of Srcpotentiation of NMDAR EPSCs in CA1
NRG1b prevents endogenous Src potentiation of NMDAR EPSCs in Prefrontal Cortex
NRG1b–ErbB4 signaling prevents TBS-induced GluN2B phosphorylation in hippocampal CA1
NRG1b does not affect LTP in Src-/- slices
EPQ(pY)EEIPIA enhancement of synaptic transmission is lost inSrc-/- slices
NRG1b signaling reduces depolarization of CA1 neurons during the period of TBS
NRG1b signaling reduces depolarization of CA1 neurons during the period of TBS
NRG1b signaling reduces depolarization of CA1 neurons during the period of TBS
Control
NRG1b
NMDAR
Glu
Mg2+AMPAR KAIR
ND2
Basal SynapticTransmission
AMPAR KAIR
Src
Glu
ND2
EnhancedSynaptic Plasticity
Src
ErbB4
ErbB4
NRG1
X
Glu
ND2
PhysiologicalSynaptic Plasticity
Src
ErbB4
NRG1
+
-
Theta BurstStimulation
Glu
ND2Src
ErbB4
SuppressedSynaptic Plasticity
NRG1
+-
Ca2+
Ca2+
Salter & Pitcher, FEBS Letters, 2011
Graham Pitcher
Declan AliRand AskalanDavid NgJon DavidowJeff GingrichYueqiao HuangLorraine KaliaGary KeilSimon BeggsKen PelkeyXuejun LiuXian-Min Yu Yutian Wang
Janice Hicks Sandra Singhroy David Wong
U of TEvelyn LambeNathalie GoodfellowJohn MacDonald
Tufts UnivKathleen Yee
UNCRichard Weinberg
U. Alabama / Georgia Health Sci. U.Lin MeiRan-Sook WooYang Z. Huang
Mt. Sinai HospitalJohn RoderYou-Ming Lu
Declan AliRand AskalanSimon BeggsJon DavidowJeff GingrichYueqiao HuangLorraine KaliaGary KeilChun KwanKen PelkeyXuejun LiuYi NongGraham Pitcher Tuan TrangXian-Min Yu Yutian WangWenbo Zhang Janice Hicks Sandra Singhroy David Wong
Mt. Sinai HospitalJohn RoderYou-Ming Lu
Yale UniversityPaul LombrosoTri-Hung Nguyen
U of T / RobartsJohn MacDonaldWei-Yang LuZhigang Xiong
Sapporo Medical Univ.Terukatsu SasakiHiroshi Aoto
U of T / UBCYutian WangWilliam JuReza Ahmadian
N I HRobert WentholdRonald Petralia
U of TEvelyn LambeNathalie Goodfellow
Tufts UnivKathleen Yee
UNCRichard Weinberg
U. Alabama / Georgia Health Sci. U.Lin MeiRan-Sook WooYang Z. Huang
PNI-induced increase in GluN2B tyrosine phosphorylation is suppressed in Src-/- mice
Liu et al. Nature Medicine 14:1325-1332, 2008
Mg2+
Cytoplasmic
2134
Glu
Cytoplasmic
N
C
Scaffolding/Signalling Proteins
YP
YP
YP
YP
YP
Phosphorylation by Src kinase
21 3 4
Gly
N
C
K+
Na+
Ca2+
PNI-induced cold sensitization reversed by Src40-49Tat
Schizophrenia Genetic Susceptibility(Neuregulin1 (NRG1) & ErbB4)
NMDAR HypofunctionPCP
Ketamine
Hippocampus&
Theta Wave (EEG)
Human ErbB4 (side)
Human ErbB4 (top)
b c
a
Time (min)
fEP
SP
slo
pe
(%
)
0
25
50
75
100
125
APV
NRG
NBQX
Neuregulin
fEP
SP
slo
pe
(%
)fE
PS
P s
lop
e (
%)
0 20 40 60 80
100
150
200
250
a b c
a b c
20 40 60 80Interval (ms)
0 250 500
Ra
tio (
P2
/P1
)
1.0
1.5
2.0
Time (min)
0 20 40 60 80
100
150
200
250
Control
Neuregulin
Time (min)
Effect of NRG-1b on NR2 Tyrosine Phosphorylation at Schaffer Collateral CA1 Synapses
pY
NR2
pY
NR2
Hahn, C-G., Nat. Med. 17:425-427, 2011
Src hypofunction induced by enhanced NRG1-ErbB4 signalingin schizophrenia
