The Biochemistry of LTP Induction From Mechanisms of Memory by J. David Sweatt, Ph.D.
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Transcript of The Biochemistry of LTP Induction From Mechanisms of Memory by J. David Sweatt, Ph.D.
The Biochemistry of LTP Induction
From Mechanisms of Memory by J. David Sweatt, Ph.D.
From Sheng and Kim
NeurotransmitterReceptor
NMDA Receptor
AMPA Receptor
K Channels
Ca++ Channels
IP3
Receptor
1
2
23
3
4
4
5
LTP induction machinery
Synaptic Infrastructure
Ca++
6Persisting
Signal
The Biochemistry of LTP Induction
1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function.
2. Mechanisms upstream of the NMDA receptor that control membrane depolarization.
3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally.
4. Feed-forward and feedback mechanisms that regulate the level of calcium attained.
5. Extrinsic signals that regulate the response to the calcium influx.
6. The mechanisms for the generation of the actual persisting biochemical signals.
Glutamate Receptors
NR1 120
NR2A 180
NR2B 180
GluR6 + 7 117
mGluR1a 200
Scaffolding and adaptors
PSD-95 95
ChapSyn110/PSD-93 110
Sap102 115
GKAP/SAPAP 95-140
Shank 200
Homer 28/45
Yotiao 200
AKAP150 150
NSF 83
PKA
PKA catalytic subunit 40
PKA-R2β 53
PKC
PKCβ 80
PKCγ 80
PKCε 90
CaM Kinase
CaM Kinase II β 60
phosph-CaM Kinase 60
Phosphatases
PP1 36
PP2A 36
PP2B(calcineurin) 61
PPs 50
PTPID/SHP2 72
Tyrosine Kinases
Src 60
PYK2 116
MAP Kinase pathway
ERK (pan ERK) 42/44
ERK1 42/44
ERK2 42
MEK1 45
MEK2 46
MKP2 43
Rsk 90
Rsk-2 90
c-Raf1 74
Small G-proteins and modulators
Rac1 21
Rap2 21
SynGAP 10,12,35,60
NF1 60,101
Other signaling molecules
Calmodulin 15
nNOS 155
PI3 Kinase 85
PLCγ 130
cPLA2 110
Citron 183
Arg3.1 55
Cell adhesion and cytoskeletal proteins
N-Cadherin 150
Desmoglein 165
β-Caternin 92
LI 200
pp120cas 120
MAP2B 280
Actin 45
α-actinin 2 110
Spectrin 240/280
Myosin (brain) 205
Tubulin 50
Coractin 80/85
CortBP-1 180/200
Clathryn heavy chain 180
Dynamin 100
Hsp-70 70
Molecule Mr (kD) Molecule Mr (kD) Molecule Mr (kD)
Husi et al. (2001) Nature Neuroscience 3: 661-669.
The Biochemistry of LTP Induction
1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function.
2. Mechanisms upstream of the NMDA receptor that control membrane depolarization.
3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally.
4. Feed-forward and feedback mechanisms that regulate the level of calcium attained.
5. Extrinsic signals that regulate the response to the calcium influx.
6. The mechanisms for the generation of the actual persisting biochemical signals.
Modulator Mechanism Effect
Src family tyrosine kinases (src, fyn) tyrosine phosphorylation enhancement
loss of Zn inhibition
Scaffolding proteins
RACK1 binding inhibitory
PSD-95 scaffolding modulatory
PKC ser/thr phosphoryation (direct) enhancement
src activation (indirect)
PKA/PP1/Yotiao phosphorylation enhancement
dephosphorylation inhibition
Cyclin dependent kinase 5 ser/thr phosphorylation enhancement
Nitric Oxide/redox sulfhydryl nitrosylation inhibition
or oxidation
Polyamines (e.g. spermine, spermidine) direct binding to a modulatory augmentation
site
Caseine kinase II ser/thr phosphorylation enhancement
modulation of polyamine effects
TABLE I – DIRECT MODULATORS OF THE NMDA RECEPTOR
Yotiao
LeptinReceptor
ApoEReceptor
EphBReceptor
NMDA Receptor
NMDA ReceptorNeurotransmitterReceptor Coupled
To PLC
NeurotransmitterReceptor CoupledTo Acetyl Choline
Leptin ApoE Ephrin B
pyk2
ERK
RACK
Src/Fyn
PSD95
Tyr
PO4PO4PI3K/MAPK
??
?
Co
mp
lex
form
atio
nSTEP
PKC
PLC
PIP
X
Ser/Thr
PO4PKA
PP1
CDK5CKII
ATP cAMP
?DAG
Receptor Modulation of the NMDA receptor
The Biochemistry of LTP Induction
1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function.
2. Mechanisms upstream of the NMDA receptor that control membrane depolarization.
3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally.
4. Feed-forward and feedback mechanisms that regulate the level of calcium attained.
5. Extrinsic signals that regulate the response to the calcium influx.
6. The mechanisms for the generation of the actual persisting biochemical signals.
Ionic Current Molecules Involved Role Mechanisms of
Modulation
K Currents
Voltage-dependent Kv4.2 (and Kv4.3) limit bpAPs ERK, PKA, CaMKII
“A” currents limit EPSP magnitude
“H” Currents NCN channels regulate excitabilitycyclic nucleotides (direct)
(HCN)
Na Currents
AMPA Receptors GluR1, GluR2 depolarize membrane PKA, CaMKII, PKC
Aka GluR-A,B
Voltage-dependent Na(v)1.6, 1.1,1.2 AP propagationPKC (decreased inactivation)
Na+ currents
Ca Currents ? – likely many AP propagation PKA
(hypothetical)
Cl Currents
GABA Receptors all GABA-A AP firing numerous
receptor subunits excitability
TABLE II – MECHANISMS UPSTREAM OF THE NMDA RECEPTOR INVOLVED IN MEMBRANE DEPOLARIZATION
Three-way Coincidence Detection
↓Kv4.2
Strong Input
Back propagatingAction Potential
ACh
CA1 Pyramidal Neuron
NMDAR
Glu
1
1
22
3
The Biochemistry of LTP Induction
1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function.
2. Mechanisms upstream of the NMDA receptor that control membrane depolarization.
3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally.
4. Feed-forward and feedback mechanisms that regulate the level of calcium attained.
5. Extrinsic signals that regulate the response to the calcium influx.
6. The mechanisms for the generation of the actual persisting biochemical signals.
Component Targets Role
Cell Adhesion Molecules
Integrins src, rho, rac, ras/MAPKs Transmembrane signaling,
Interactions with extracellular
matrix, NMDAR regulation
MLCK, FAK? spine morphology?
Syndecan-3 fyn, NMDAR signaling from matrix heparan
sulfates to the NMDA receptor
N-Cadherin other Cadherins, spine morphology?
cytoskeleton Pre-post adhesion?
Actin Cytoskeleton/Associated Proteins
Rho membrane/cytoskeleton regulate synaptic structure
interactions
Cdk5 NMDA receptor increase NMDA receptor function
Filamin K channels K channel localization
Presynaptic Processes
Glutamate release synaptic glutamate NMDA receptor activation
Glutamate re-uptake synaptic glutamate limiting NMDA receptor
desensitization
TABLE III – COMPONENTS OF THE SYNAPTIC INFRASTRUCTURE NECESSARY FOR NMDA RECEPTOR FUNCTION
Component Targets Role
Anchoring/Interacting proteins
PSD-95 receptors, postsynaptic organization
signal transduction mechs
nNOS, SynGAP, GKAP
NMDA receptor multiple proteins effector localization, structural
organization
Rack1/fyn NMDA receptordirect regulation of NMDA receptor
Shank/HOMER metabotropic receptors effector localization, cytoskeleton
GRIP AMPA receptors, postsynaptic organization
PICK-1/PKC
AKAP PKA, PP2Bkinase and phosphatase localization
CaMKII signal transductionregulate likelihood of LTP induction
TABLE III – COMPONENTS OF THE SYNAPTIC INFRASTRUCTURE NECESSARY FOR NMDA RECEPTOR FUNCTION ( Continued)
NMDAR NR2
NMDARNR2
AMPARGluR2,GluR3
AMPAR
GAPPSD-95
rap
actin
n-NOS
SynGAP
GKAP PSD95
GKAP
ShankHomer
IP3R
PLC
actinras
IP3 + DAG
SPAR
cortactin-
Spectrin
PICK-1
PKC
GRIP
NSFGRASP1
(GEF for ras)
ras
PKA PKC
AKAP79 PP2B
SAP97
CamKII
β-AR
ReceptorTrafficking liprin
Group I mGluR
PSD-95 as an Anchoring Protein for NMDA Receptors
From Sheng and Kim
Fig. 1. RIM1 and the priming of synaptic vesicle fusion. (a) After docking, synaptic vesicles (SV) are tethered at the active zone by binding of Rab3 to the N-terminal (N) of RIM1 (Rab3-interactive molecule-1). Munc-13 is recruited to the active zone by activity of phospholipase C (PLC) and the second messenger diacylglycerol (DAG). Munc-18 binding to syntaxin (Syntx) keeps syntaxin in a `closed' conformation that cannot bind SNAP-25 (synapstosome-associated protein-25). (b) Activation of second-messenger pathways – such as those involving Ca2+, adenylate cyclase (AC), cAMP and protein kinase A (PKA) – during induction of short-term plasticity leads to a switch in the binding partners of RIM1. Munc-13-1 binds to N-terminal RIM1, competitively inhibiting the binding of Rab3 to RIM1. Thus, a new tethering mechanism holds the SVs at the active zone, as synaptotagmin1/2 (Synat) binds to the C-terminal RIM domains in a Ca2+-dependent manner. Binding of munc-13 to syntaxin removes munc-18 and converts syntaxin's structure to an open conformation. (c) Proximity of synaptotagmin to the plasma membrane, conversion of syntaxin by Munc-13-1 to an open conformation that can interact with SNAP-25, and further increase in cytoplasmic free Ca2+ levels, promote the formation of the synaptobrevin (Syb)–syntaxin–SNAP-25 complex that is required for fusion.
Three Pools of F-Actin in Synaptic Spines
The upper panels are single computed slices through electron tomographic volumes of spines labeled for F-actin using phaloidin-eosin photo conversion, from hippocampus CA1 (A) and cerebellar cortex molecular layer (B) (see Capani et al., 2001 ). Labeling is concentrated between the lamellae of the spine apparatus (SA) and the postsynaptic density (arrowheads). Bundles of actin are seen traversing between these entities (large arrow). In Purkinje cells, which have no spine apparatus, actin filaments fill the head and also can be followed between the smooth ER and the postsynaptic membrane (large arrow). Diffuse staining for actin is also seen (asterisks). The stereo computer graphic reconstruction in the bottom panel is of the CA1 synapse and shows actin bundles (blue) as well as the spine apparatus (yellow) and the postsynaptic density (purple). These figures were kindly provided by Dr. Mark Ellisman.
Figure 1. LIMK Influences Postsynaptic and Presynaptic Function through Modulation of Actin FilamentsDendritic spines are made up of a head, neck, and postsynaptic density (PSD). Within the PSD, scaffold proteins such as Homer, PSD-95, and Shank, as well as others not described here, link the actin cytoskeleton to postsynaptic receptors including AMPA and NMDA glutamate receptors. Results in this issue of Neuron by Meng et al. (2002 ) demonstrate that LIMK-1 is partially responsible for proper dendritic morphology and long-term potentiation (LTP), presumably via its effect on actin filament dynamics, through phosphorylation and inactivation of ADF/cofilin (AC). In LIMK-1−/− mice, the morphology of dendritic spines is altered. The spines have a thicker neck and smaller postsynaptic density length and smaller spine area. Results presented by Meng et al. (2002 ) also reveal that the LIMK-1−/− mice have enhanced basal release of presynaptic vesicles and an enhanced synaptic depression, suggesting a role for LIMK-1 (and most likely actin dynamics) in neurotransmitter release. Figure by Patrick D. Sarmiere and James R. Bamburg
Presynaptic
Postsynaptic
NMDA Receptor
Retrograde Signaling
Integrins
rho
rac
FAK
MLCK
ras
α-actinin
Src/fyn
ERK
β subunit
filamin
?
?
cdk5
talin
vinculin
?
Kv4.2 Channel
actin
actin
actin
DynamicRegulation
Integrins
Extracellular Matrix
Interactions among Integrins and Intracellular Effectors
The Biochemistry of LTP Induction
1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function.
2. Mechanisms upstream of the NMDA receptor that control membrane depolarization.
3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally.
4. Feed-forward and feedback mechanisms that regulate the level of calcium attained.
5. Extrinsic signals that regulate the response to the calcium influx.
6. The mechanisms for the generation of the actual persisting biochemical signals.
Molecule/Organelle Role Modulator/Regulator
VDCCs augment NMDAR-dependent PKA
Ca influx
Ca influx due to bpAPs
regulate ERK activation
Endoplasmic Reticulum Ca efflux from ER, limit LTP? PLC-coupled receptors
(Ca ATPase/IP3R/RyR)
Presynaptic Mitochondria regulate presynaptic Ca levels unknown
TABLE IV – CALCIUM FEEDBACK AND FEED-FORWARD MECHANISMS
The Biochemistry of LTP Induction
1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function.
2. Mechanisms upstream of the NMDA receptor that control membrane depolarization.
3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally.
4. Feed-forward and feedback mechanisms that regulate the level of calcium attained.
5. Extrinsic signals that regulate the response to the calcium influx.
6. The mechanisms for the generation of the actual persisting biochemical signals.
Regulatory System Molecules Involved Role
The cAMP Gate PKA/PP1/I1/PP2B Phosphatase Inhibition
Augmented Kinase Signaling
The PKC/Neurogranin PLC/PKC/Neurogranin/CaM Augmenting CaMKII Activation
System Augmenting Ca-sensitive Cyclase
TABLE V – EXTRINSIC SIGNALS MODULATING THE CALCIUM RESPONSE
Model for the cAMP Gate
Sweatt (2001) Curr. Biol. 11:R391-394.
Phospholipase CNeurogranin
Neurogranin
PO4
+
DAG
PKC
Calmodulin
Calmodulin
MetabotropicReceptor
PKC Phosphorylation of Neurogranin
AugmentedPKC
cAMPGATE
Initial Ca++Signal
IncreasedCa++/CaM
Augmented CaMKIIActivity
AdenylylCyclase
NMDARN
euro
gra
nin
DAG
Cyclase CoupledReceptors
MetabotropicReceptors
The PKC/Neurogranin system and the cAMP Gate
The Biochemistry of LTP Induction
1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function.
2. Mechanisms upstream of the NMDA receptor that control membrane depolarization.
3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally.
4. Feed-forward and feedback mechanisms that regulate the level of calcium attained.
5. Extrinsic signals that regulate the response to the calcium influx.
6. The mechanisms for the generation of the actual persisting biochemical signals.
Four-way Coincidence Detection
↓Kv4.2
Strong Input
Back propagatingAction Potential
ACh
CA1 Pyramidal Neuron
NMDAR
Glu
1
1
22
3
cAMPGATE
Norepinephrine
4
4
The Biochemistry of LTP Induction
From Mechanisms of Memory by J. David Sweatt, Ph.D.