Abstract
The related small GTPases Ras and Rap1 are important for signaling synaptic AMPA receptor (-R) trafficking during long-term potentiation (LTP) and long-term depression (LTD), respectively. Rap2, which shares 60% identity to Rap1, is present at excitatory synapses, but its functional role is unknown. Here, we report that Rap2 activity, stimulated by NR2A-containing NMDA-R activation, depresses AMPA-R-mediated synaptic transmission via activation of JNK rather than Erk1/2 or p38 MAPK. Moreover, Rap2 controls synaptic removal of AMPA-Rs with long cytoplasmic termini during depotentiation. Thus, Rap2-JNK pathway, which opposes the action of the NR2A-containing NMDA-R-stimulated Ras-ERK1/2 signaling and complements the NR2B-containing NMDA-R-stimulated Rap1-p38 MAPK signaling, channels the specific signaling for depotentiating central synapses.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Animals, Newborn
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Blotting, Western / methods
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Cells, Cultured
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Drug Interactions
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Electric Stimulation / methods
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Fluorescent Antibody Technique / methods
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Green Fluorescent Proteins / metabolism
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Hippocampus / cytology
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In Vitro Techniques
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JNK Mitogen-Activated Protein Kinases / classification
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Long-Term Synaptic Depression / physiology*
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Magnesium / pharmacology
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Models, Neurological
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Mutagenesis / physiology
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N-Methylaspartate / pharmacology
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Neurons / drug effects
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Neurons / physiology
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Patch-Clamp Techniques / methods
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Phosphorylation / drug effects
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Rats
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Receptors, AMPA / metabolism*
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Recombinant Proteins / biosynthesis
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Synaptic Transmission / physiology*
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Time Factors
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Transfection / methods
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Valine / analogs & derivatives*
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Valine / pharmacology
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
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rap GTP-Binding Proteins / metabolism*
Substances
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Receptors, AMPA
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Recombinant Proteins
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Green Fluorescent Proteins
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N-Methylaspartate
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2-amino-5-phosphopentanoic acid
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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JNK Mitogen-Activated Protein Kinases
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rap GTP-Binding Proteins
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Valine
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Magnesium
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glutamate receptor ionotropic, AMPA 2
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glutamate receptor ionotropic, AMPA 1