The Biochemistry of LTP Induction From Mechanisms of Memory by J. David Sweatt, Ph.D.

LTP induction machinery Neurotransmitter Receptor Synaptic Infrastructure 5 3 2 K Channels 3 4 IP3 Receptor Ca++ NMDA Receptor 1 Persisting Signal 6 2 Ca++ Channels AMPA Receptor 4

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

Interactions among Integrins and Intracellular Effectors 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 Dynamic Regulation Extracellular Matrix

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

Model for the cAMP Gate Sweatt (2001) Curr. Biol. 11:R391-394.

PKC Phosphorylation of Neurogranin Metabotropic Receptor Neurogranin Phospholipase C Calmodulin DAG PKC Neurogranin PO4 + Calmodulin

The PKC/Neurogranin system and the cAMP Gate Metabotropic Receptors Cyclase Coupled Receptors DAG cAMP GATE Augmented PKC NMDAR Adenylyl Cyclase Initial Ca++ Signal Neurogranin Augmented CaMKII Activity Increased Ca++/CaM

Four Way Coincidence Detection CA1 Pyramidal Neuron Strong Input 1 Back propagating Action Potential 1 2 ↓Kv4.2 2 ACh Glu 3 4 NMDAR cAMP GATE Norepinephrine 4

MAPK as a Signal Integrator Controlling Kv4.2 Watanabe, Zaki and O’Dell (2000) J. Neurosci. 20:5924-5931.

Coupling of Receptors to Intracellular Messengers The cAMP System The PLC System Adenylyl Cyclase α γ β GTP GDP ATP cAMP Substrate PO4 Reg Cat. Ion Channels “Gs” Protein Receptor cAMP-Dependent Protein Kinase (PKA) Receptor α γ β GTP GDP “Go” Protein PLC IP3 DAG Ca++ PKC Substrate PO4 PIP2

ras ras Activation of ras Inactive Active GAPs GEFs PO4 GTP Hydrolysis GDP GTP + + GAPs GTPase Activating Proteins e.g. NF1, SynGAP GTP GEFs Guanine Nucleotide Exchange Factor Proteins e.g. SOS, cAMP GEF, Ca2+/DAG GEF, ras GRF Weeber and Sweatt. Neuron 33:845-848.

Husi et al. (2001) Nature Neuroscience 3: 661-669. Molecule Mr (kD) Molecule Mr (kD) Molecule Mr (kD) Glutamate Receptors NR1 120 NR2A 180 NR2B GluR6 + 7 117 mGluR1a 200 Phosphatases PP1 36 PP2A PP2B(calcineurin) 61 PPs 50 PTPID/SHP2 72 Other signaling molecules Calmodulin 15 nNOS 155 PI3 Kinase 85 PLCγ 130 cPLA2 110 Citron 183 Arg3.1 55 Scaffolding and adaptors PSD-95 95 ChapSyn110/PSD-93 110 Sap102 115 GKAP/SAPAP 95-140 Shank 200 Homer 28/45 Yotiao AKAP150 150 NSF 83 Tyrosine Kinases Src 60 PYK2 116 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 MAP Kinase pathway ERK (pan ERK) 42/44 ERK1 ERK2 42 MEK1 45 MEK2 46 MKP2 43 Rsk 90 Rsk-2 c-Raf1 74 PKA PKA catalytic subunit 40 PKA-R2β 53 PKC PKCβ 80 PKCγ PKCε 90 Small G-proteins and modulators Rac1 21 Rap2 SynGAP 10,12,35,60 NF1 60,101 CaM Kinase CaM Kinase II β 60 phosph-CaM Kinase Husi et al. (2001) Nature Neuroscience 3: 661-669.