title: NMDA receptor-mediated PIP5K activation to produce PI(4,5)P₂ is essential for AMPA receptor endocytosis during LTD.
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.
authors.affiliation: Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Ten-nohdai, Tsukuba 305-8571, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Unoki
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsuda
authors.forename: Wataru
authors.initials: W
authors.lastname: Kakegawa
authors.forename: Ngo Thai Bich
authors.initials: NT
authors.lastname: Van
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kohda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Funakoshi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Michisuke
authors.initials: M
authors.lastname: Yuzaki
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kanaho
mesh_terms: D000199:Actins / Q000378:metabolism; D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009154:Mutation / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000199:Actins; D033962:Adaptor Protein Complex 2; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D051528:Guanylate Kinases; C104722:glutamate receptor ionotropic, AMPA 2