Rap2-JNK removes synaptic AMPA receptors during depotentiation.
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.
Zhu
Yinghua
Y
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Pak
Daniel
D
Qin
Yi
Y
McCormack
Stefanie G
SG
Kim
Myung J
MJ
Baumgart
Joel P
JP
Velamoor
Vanisree
V
Auberson
Yves P
YP
Osten
Pavel
P
van Aelst
Linda
L
Sheng
Morgan
M
Zhu
J Julius
JJ
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000145:classification / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008274:Magnesium / Q000494:pharmacology; D008959:Models, Neurological; D016296:Mutagenesis / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis; D009435:Synaptic Transmission / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D020668:rap GTP-Binding Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D049452:Green Fluorescent Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008274:Magnesium; D016202:N-Methylaspartate; D018091:Receptors, AMPA; D011994:Recombinant Proteins; D014633:Valine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D020668:rap GTP-Binding Proteins; C056639:2-amino-5-phosphopentanoic acid; C104722:glutamate receptor ionotropic, AMPA 2