Chapter 8:The NMDA Receptor

From Mechanisms of Memory, second editionBy J. David Sweatt, Ph.D.

The NMDA Receptor

Figure 1

Loss of the NMDA Receptor Selectivity in Hippocampal Area CA1 Leads to Selective Deficits in LTP

Figure 2

A

B

Loss of the NMDA Receptor in Area CA1 Blocks Learning in the Morris Water Maze

Figure 3

NMDA Receptors are Involved in Synaptic Plasticity

Figure 4

NMDA Receptor and Binding Sites for Regulatory Molecules

Direct Modulators of the NMDA Receptor

 

modulation of polyamine effects

enhancementser/thr phosphorylationCaseine kinase II

Site augmentation direct binding to a modulatoryPolyamines (e.g. spermine, spermidine)

 

or oxidation

 

inhibitionsulfhydryl nitrosylationNitric Oxide/Reactive Oxygen Species

   

enhancementser/thr phosphorylationCyclin dependent kinase 5

   

inhibitiondephosphorylation   

enhancement PhosphorylationPKA/PP1/Yotiao

 

 

  

enhancementsrc activation (indirect)

 

enhancementser/thr phosphoryation (direct)

PKC

    

modulatoryScaffoldingPSD-95 

   

inhibitoryBindingRACK1 

  Scaffolding proteins

    

 loss of Zn inhibition

 enhancementtyrosine phosphorylationSrc family tyrosine kinases (src, fyn)

EffectMechanismModulator

Table 1

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)

Fig

ure

5Summary of Molecular Composition of the NMDAR Supramolecular Complex

Figure 6

ModulatoryNeurotransmitter

Receptor

NMDA Receptor

AMPA Receptor

K Channels

Ca++ Channels

1

2

23

3

2

2Synaptic Infrastructure

Ca++

LTP Induction Machinery

TABLE II – MECHANISMS UPSTREAM OF THE NMDA RECEPTOR INVOLVED IN MEMBRANE DEPOLARIZATION

 excitabilityreceptor subunits  

numerousAP firingall GABA-AGABA Receptors 

   Cl Currents

 (hypothetical)   

PKAAP propagation? – likely manyCa Currents

   Na+ currents 

PKC (decreased inactivation)AP propagationNa(v)1.6, 1.1,1.2Voltage-dependent 

    

  Aka GluR-A,B  

PKA, CaMKII, PKCdepolarize membraneGluR1, GluR2AMPA Receptors 

   Na Currents

  

cyclic nucleotides (direct)regulate excitabilityNCN channels (HCN)“H” Currents 

 limit EPSP magnitude “A” currents 

ERK, PKA, CaMKIIlimit bpAPsKv4.2 (and Kv4.3)Voltage-dependent  

   K Currents

Mechanisms of ModulationRoleMolecules InvolvedIonic Current

desensitization   

limiting NMDA receptorsynaptic glutamateGlutamate re-uptake 

NMDA receptor activationsynaptic glutamateGlutamate release 

  Presynaptic Processes

K channel localizationK channelsFilamin 

increase NMDA receptor functionNMDA receptorCdk5 

 interactions  

regulate synaptic structuremembrane/cytoskeletonRho 

Actin Cytoskeleton/Associated Proteins 

Pre-post adhesion?cytoskeleton  

spine morphology?other Cadherins, N-Cadherin 

sulfates to the NMDA receptor   

signaling from matrix heparan fyn, NMDARSyndecan-3 

spine morphology?MLCK, FAK?  

matrix, NMDAR regulation   

Interactions with extracellular   

Transmembrane signaling,src, rho, rac, ras/MAPKsIntegrins 

  Cell Adhesion Molecules

RoleTargetsComponent

TABLE III – COMPONENTS OF THE SYNAPTIC INFRASTRUCTURE NECESSARY FOR NMDA RECEPTOR FUNCTION

TABLE III – COMPONENTS OF THE SYNAPTIC INFRASTRUCTURE NECESSARY FOR NMDA RECEPTOR FUNCTION -- CONTINUED

regulate likelihood of LTP inductionsignal transductionCaMKII 

kinase and phosphatase localizationPKA, PP2BAKAP 

 PICK-1/PKC  

postsynaptic organizationAMPA receptors,GRIP 

effector localization, cytoskeletonmetabotropic receptorsShank/HOMER 

direct regulation of NMDA receptorNMDA receptorRack1/fyn 

 nNOS, SynGAP, GKAP  

 signal transduction mechs  

postsynaptic organizationreceptors, PSD-95 

  Anchoring/Interacting proteins

Figure 7

Yotiao

LeptinReceptor

ApoEReceptor

EphBReceptor

NMDA Receptor

NMDA ReceptorNeurotransmitterReceptor Coupled

To PLC

NeurotransmitterReceptor CoupledTo Acetylcholine

Leptin ApoE Ephrin B

pyk2

ERK

RACK

Src/Fyn

PSD95

Tyr

PO4PO4PI3K/MAPK

??

?

Co

mp

lex

form

atio

nSTEP

PKC

PLC

PIPX

Ser/Thr

PO4PKA

PP1

CDK5CKII

ATP cAMP

?DAG

Receptor Modulation of the NMDA Receptor

Figure 8

Presynaptic

Postsynaptic

NMDA Receptor

Retrograde Signaling

Integrins

rho

rac

FAK

MLCK

ras

α-actinin

Src/fyn

ERK

?

?

cdk5

talin

vinculin

?

Kv4.2 Channel

actin

actin

actin

DynamicRegulation

IntegrinsExtracellular

Matrix

β subunit

filamin

Interactions among Integrins and Intracellular Effectors

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)

rasPKA PKC

AKAP79 PP2B

SAP97

CamKII

β-AR

ReceptorTrafficking liprin

Group I mGluR

Fig

ure

9

PSD-95 as an Anchoring Protein