Abstract
NMDA receptor activation leads to clathrin-dependent endocytosis of postsynaptic AMPA receptors. Although this process controls long-term depression (LTD) induction in the hippocampus, how it is regulated by neuronal activities is not completely clear. Here, we show that Ca²⁺ influx through the NMDA receptor activates calcineurin and protein phosphatase 1 to dephosphorylate phosphatidylinositol 4-phosphate 5-kinaseγ661 (PIP5Kγ661), the major phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂)-producing enzyme in the brain. Bimolecular fluorescence complementation analysis revealed that the dephosphorylated PIP5Kγ661 became associated with the clathrin adaptor protein complex AP-2 at postsynapses in situ. NMDA-induced AMPA receptor endocytosis and low-frequency stimulation-induced LTD were completely blocked by inhibiting the association between dephosphorylated PIP5Kγ661 and AP-2 and by overexpression of a kinase-dead PIP5Kγ661 mutant in hippocampal neurons. Furthermore, knockdown of PIP5Kγ661 inhibited the NMDA-induced AMPA receptor endocytosis. Therefore, NMDA receptor activation controls AMPA receptor endocytosis during hippocampal LTD by regulating PIP5Kγ661 activity at postsynapses.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Adaptor Protein Complex 2 / metabolism
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Animals
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Animals, Newborn
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Biophysics
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Cells, Cultured
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Disks Large Homolog 4 Protein
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Dose-Response Relationship, Drug
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Electric Stimulation
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Embryo, Mammalian
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Endocytosis / drug effects
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Endocytosis / genetics
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Endocytosis / physiology*
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Guanylate Kinases / metabolism
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Hippocampus / cytology
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Immunoprecipitation
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In Vitro Techniques
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Long-Term Synaptic Depression / drug effects
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Long-Term Synaptic Depression / genetics
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Long-Term Synaptic Depression / physiology*
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred ICR
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Mutation / genetics
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N-Methylaspartate / pharmacology
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects
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Neurons / physiology*
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Patch-Clamp Techniques
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Protein Transport / drug effects
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Protein Transport / genetics
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RNA, Small Interfering
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Receptors, AMPA / genetics
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Receptors, AMPA / metabolism*
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Receptors, N-Methyl-D-Aspartate / metabolism
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Time Factors
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Transfection
Substances
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Actins
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Adaptor Protein Complex 2
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Membrane Proteins
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Nerve Tissue Proteins
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RNA, Small Interfering
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Receptors, AMPA
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Receptors, N-Methyl-D-Aspartate
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Green Fluorescent Proteins
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N-Methylaspartate
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Phosphotransferases (Alcohol Group Acceptor)
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1-phosphatidylinositol-4-phosphate 5-kinase
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Guanylate Kinases
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glutamate receptor ionotropic, AMPA 2