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The Biochemistry of LTP Induction

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. IP 3 Receptor. Ca ++. NMDA Receptor. 1. Persisting Signal. 6. 2. Ca ++ Channels.

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The Biochemistry of LTP Induction

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

  2. 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

  3. Receptor Modulation of the NMDA receptor 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 Acetyl Choline Neurotransmitter Receptor Coupled To PLC NMDA Receptor

  4. Presynaptic Retrograde Signaling Integrins Kv4.2 Channel NMDA Receptor 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 Interactions among Integrins and Intracellular Effectors

  5. PSD-95 as an Anchoring Protein for NMDA Receptors NMDAR NR2 NMDAR NR2 GAP PSD95 PSD-95 n-NOS GKAP Spectrin GKAP SPAR Shank SynGAP Homer actin cortactin rap - IP3R Group I mGluR actin ras 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

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

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

  8. 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

  9. 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

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

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

  12. + + Activation of ras Inactive Active PO4 ras ras 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.

  13. Husi et al. (2001) Nature Neuroscience 3: 661-669.

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