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The Biochemistry of LTP
Induction
From Mechanisms of Memory by
J. David Sweatt, Ph.D.
LTP induction machinery
Synaptic
Infrastructure
Neurotransmitter
5 Receptor
3
2
K Channels
3
4
IP3
Receptor
Ca++
NMDA 1
Receptor
AMPA 2
Receptor
6
Ca++ Channels
4
Persisting
Signal
Receptor Modulation of the NMDA receptor
NMDA Receptor
Leptin
ApoE
Leptin
Receptor
ApoE
Receptor
Ephrin B
EphB
Receptor
PSD95
Tyr
STEP
PO4
RACK
PI3K/MAPK
Complex
formation
PO4
?
?
ERK
?
Src/Fyn
pyk2
CDK5
CKII
?
ATP
cAMP
PKC
PKA
DAG
PP1
PO4
Yotiao
Ser/Thr
PL
C
PIP
X
Neurotransmitter
Receptor Coupled
To Acetyl Choline
NMDA Receptor
Neurotransmitter
Receptor Coupled
To PLC
Interactions among Integrins and Intracellular Effectors
Presynaptic
Retrograde Signaling
Kv4.2 Channel
Integrins
NMDA Receptor
Integrins
?
β subunit
Src/fyn
filamin
rho
ras
α-actinin
talin
vinculin
cdk5
Postsynaptic
ERK
Extracellular
Matrix
rac
FAK ?
MLCK ?
Dynamic
Regulation
PSD-95 as an Anchoring Protein for NMDA Receptors
NMDAR
NR2
NMDAR
NR2
GAP
PSD-95
n-NOS
PSD95
GKAP
Spectrin
GKAP
SPAR
Shank
SynGAP
-
rap
Homer
cortactin
IP3R
ras
Group I
mGluR
PLC
IP3 + DAG
CamKII
Receptor
Trafficking
PKC
PKA
liprin
ras
AKAP79
PKC
PP2B
NSF
PICK-1
GRIP
AMPAR
GluR2,GluR3
GRASP1
(GEF for ras)
SAP97
β-AR
AMPAR
Model for the cAMP Gate
Sweatt (2001) Curr. Biol. 11:R391-394.
PKC Phosphorylation of Neurogranin
Metabotropic
Receptor
Neurogranin
Calmodulin
PKC
Neurogranin
PO4
+
Calmodulin
Phospholipase C
DAG
The PKC/Neurogranin system and the cAMP Gate
Metabotropic
Receptors
NMDAR
Initial Ca++
Signal
cAMP
GATE
Augmented
PKC
Neurogranin
DAG
Cyclase Coupled
Receptors
Increased
Ca++/CaM
Adenylyl
Cyclase
Augmented
CaMKII
Activity
Four Way Coincidence Detection
CA1 Pyramidal Neuron
Strong Input
Back propagating
Action Potential
1
2
2
3
↓Kv4.2
ACh
Glu
NMDAR
4
cAMP
GATE
Norepinephrine
4
1
MAPK as a Signal Integrator Controlling Kv4.2
GF R
PKC
Ras
Grb2
Rap1
S os
PK A
AC
B-Raf
Raf-1
PKA
MEK
p42mapk
Effectors
Watanabe, Zaki and O’Dell (2000) J. Neurosci. 20:5924-5931.
Coupling of Receptors to Intracellular Messengers
The PLC System
The cAMP System
“Gs” Protein
α
Adenylyl
Cyclase
GTP
ATP
γ
“Go” Protein
Receptor
α
β
PLC
GDP
GTP
γ
Receptor
β
GDP
PIP2
cAMP
Ca++
cAMP-Dependent
Protein Kinase (PKA)
IP3
DAG
Reg Cat.
Ion Channels
PKC
Reg Cat.
PO4
Substrate
PO4
Substrate
Activation of ras
Inactive
rasGDP
PO4
GTP Hydrolysis
+
GAPs
GTPase Activating Proteins
e.g. NF1, SynGAP
Active
rasGTP
+
GTP
GEFs
Guanine Nucleotide
Exchange Factor Proteins
e.g. SOS, cAMP GEF,
Ca2+/DAG GEF, ras GRF
Weeber and Sweatt. Neuron 33:845-848.
Molecule
Mr (kD)
Glutamate Receptors
Molecule
NR1
120
PP1
36
Calmodulin
NR2A
180
PP2A
36
nNOS
NR2B
180
PP2B(calcineurin)
61
PI3 Kinase
GluR6 + 7
117
PPs
50
PLCγ
130
mGluR1a
200
PTPID/SHP2
72
cPLA2
110
Citron
183
Arg3.1
55
Scaffolding and adaptors
PSD-95
Tyrosine Kinases
95
ChapSyn110/PSD-93
110
Sap102
115
GKAP/SAPAP
95-140
Shank
200
Homer
28/45
Yotiao
200
AKAP150
150
NSF
Mr (kD)
Phosphatases
83
PKA
Src
60
PYK2
Molecule
Mr (kD)
Other signaling molecules
150
165
ERK (pan ERK)
42/44
Desmoglein
ERK1
42/44
β-Caternin
ERK2
42
LI
200
MEK1
45
pp120cas
120
MEK2
46
MAP2B
280
MKP2
43
Actin
Rsk
90
α-actinin 2
40
Rsk-2
90
Spectrin
PKA-R2β
53
c-Raf1
74
Myosin (brain)
Tubulin
Small G-proteins and modulators
PKCβ
80
Rac1
21
Coractin
PKCγ
80
Rap2
21
CortBP-1
PKCε
90
SynGAP
CaM Kinase
NF1
CaM Kinase II β
60
phosph-CaM Kinase
60
85
N-Cadherin
PKA catalytic subunit
PKC
155
Cell adhesion and cytoskeletal
proteins
116
MAP Kinase pathway
15
10,12,35,60
60,101
92
45
110
240/280
205
50
80/85
180/200
Clathryn heavy chain
180
Dynamin
100
Hsp-70
70
Husi et al. (2001) Nature Neuroscience 3: 661-669.