Chapter 8: The NMDA Receptor

1. Chapter 8: The NMDA Receptor From Mechanisms of Memory, second edition By J. David Sweatt, Ph.D.

2. The NMDA Receptor

3. Loss of the NMDA Receptor Selectivity in Hippocampal Area CA1 Leads to Selective Deficits in LTP Figure 1

4. Loss of the NMDA Receptor in Area CA1 Blocks Learning in the Morris Water Maze A B Figure 2

5. NMDA Receptors are Involved in Synaptic Plasticity Figure 3

6. NMDA Receptor and Binding Sites for Regulatory Molecules Figure 4

7. 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 ser/thr phosphoryation (direct) enhancement PKC src activation (indirect) enhancement Phosphorylation enhancement PKA/PP1/Yotiao inhibition dephosphorylation Cyclin dependent kinase 5 ser/thr phosphorylation enhancement or oxidation sulfhydryl nitrosylation Nitric Oxide/Reactive Oxygen Species inhibition Site augmentation Polyamines (e.g. spermine, spermidine) direct binding to a modulatory ser/thr phosphorylation enhancement Caseine kinase II modulation of polyamine effects Direct Modulators of the NMDA Receptor Table 1

8. Molecule Mr (kD) Molecule Mr (kD) Molecule Mr (kD) Phosphatases Other signaling molecules Glutamate Receptors PP1 36 Calmodulin 15 NR1 120 PP2A 36 nNOS 155 NR2A 180 PP2B(calcineurin) 61 PI3 Kinase 85 NR2B 180 PPs 50 PLCγ 130 GluR6 + 7 117 PTPID/SHP2 72 cPLA2 110 mGluR1a 200 Citron 183 Scaffolding and adaptors Tyrosine Kinases Arg3.1 55 PSD-95 95 Src 60 Cell adhesion and cytoskeletal proteins ChapSyn110/PSD-93 110 PYK2 116 Sap102 115 MAP Kinase pathway N-Cadherin 150 GKAP/SAPAP 95-140 ERK (pan ERK) 42/44 Desmoglein 165 Shank 200 ERK1 42/44 β-Caternin 92 Homer 28/45 ERK2 42 LI 200 Yotiao 200 MEK1 45 pp120cas 120 AKAP150 150 MEK2 46 MAP2B 280 NSF 83 MKP2 43 Actin 45 PKA Rsk 90 α-actinin 2 110 PKA catalytic subunit 40 Rsk-2 90 Spectrin 240/280 PKA-R2β 53 c-Raf1 74 Myosin (brain) 205 PKC Tubulin 50 Small G-proteins and modulators PKCβ 80 Coractin 80/85 Rac1 21 PKCγ 80 CortBP-1 180/200 Rap2 21 PKCε 90 Clathryn heavy chain 180 SynGAP 10,12,35,60 CaM Kinase Dynamin 100 NF1 60,101 CaM Kinase II β 60 Hsp-70 70 phosph-CaM Kinase 60 Summary of Molecular Composition of the NMDAR Supramolecular Complex Figure 5

9. Modulatory Neurotransmitter Receptor Synaptic Infrastructure 2 3 2 K Channels 3 Ca++ NMDA Receptor 1 2 Ca++ Channels AMPA Receptor 2 LTP Induction Machinery Figure 6

10. TABLE II – MECHANISMS UPSTREAM OF THE NMDA RECEPTOR INVOLVED IN MEMBRANE DEPOLARIZATION 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 (HCN) regulate excitability cyclic nucleotides (direct) 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 propagation PKC (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

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

12. TABLE III – COMPONENTS OF THE SYNAPTIC INFRASTRUCTURE NECESSARY FOR NMDA RECEPTOR FUNCTION -- CONTINUED Anchoring/Interacting proteins PSD-95 receptors, postsynaptic organization signal transduction mechs nNOS, SynGAP, GKAP Rack1/fyn NMDA receptor direct regulation of NMDA receptor Shank/HOMER metabotropic receptors effector localization, cytoskeleton GRIP AMPA receptors, postsynaptic organization PICK-1/PKC AKAP PKA, PP2B kinase and phosphatase localization CaMKII signal transduction regulate likelihood of LTP induction

13. Leptin ApoE Ephrin B NMDA Receptor Leptin Receptor ApoE Receptor EphB Receptor PSD95 Tyr RACK PI3K/MAPK PO4 PO4 ? STEP ? ERK Complex formation ? Src/Fyn pyk2 CDK5 CKII ? DAG PKC PP1 PKA PO4 ATP cAMP Yotiao PLC Ser/Thr PIPX Neurotransmitter Receptor Coupled To Acetylcholine Neurotransmitter Receptor Coupled To PLC NMDA Receptor Receptor Modulation of the NMDA Receptor Figure 7

14. Presynaptic Interactions among Integrins and Intracellular Effectors Retrograde Signaling Kv4.2 Channel NMDA Receptor Integrins Extracellular Matrix Integrins β subunit ? rho Src/fyn ras filamin rac α-actinin ? FAK talin MLCK ? vinculin ERK cdk5 Dynamic Regulation actin actin actin Postsynaptic Figure 8

15. NMDAR NR2 NMDAR NR2 GAP PSD95 PSD-95 n-NOS GKAP Spectrin GKAP SPAR Shank SynGAP Homer actin cortactin rap - IP3R actin ras Group I mGluR PLC IP3 + DAG CamKII PKA PKC Receptor Trafficking PKC liprin ras AKAP79 PP2B NSF SAP97 GRASP1 (GEF for ras) PICK-1 GRIP β-AR AMPAR GluR2,GluR3 AMPAR PSD-95 as an Anchoring Protein Figure 9