RRC ID 28594
Author Unoki T, Matsuda S, Kakegawa W, Van NT, Kohda K, Suzuki A, Funakoshi Y, Hasegawa H, Yuzaki M, Kanaho Y.
Title NMDA receptor-mediated PIP5K activation to produce PI(4,5)P₂ is essential for AMPA receptor endocytosis during LTD.
Journal Neuron
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.
Volume 73(1)
Pages 135-48
Published 2012-1-12
DOI 10.1016/j.neuron.2011.09.034
PII S0896-6273(11)00925-1
PMID 22243752
MeSH Actins / metabolism Adaptor Protein Complex 2 / metabolism Animals Animals, Newborn Biophysics Cells, Cultured Disks Large Homolog 4 Protein Dose-Response Relationship, Drug Electric Stimulation Embryo, Mammalian Endocytosis / drug effects Endocytosis / genetics Endocytosis / physiology* Enzyme Inhibitors / pharmacology Excitatory Amino Acid Agonists / pharmacology Gene Expression Regulation / drug effects Gene Expression Regulation / genetics Green Fluorescent Proteins / genetics Guanylate Kinases / metabolism Hippocampus / cytology Immunoprecipitation In Vitro Techniques Long-Term Synaptic Depression / drug effects Long-Term Synaptic Depression / genetics Long-Term Synaptic Depression / physiology* Membrane Proteins / metabolism Mice Mice, Inbred ICR Mutation / genetics N-Methylaspartate / pharmacology Nerve Tissue Proteins / metabolism Neurons / drug effects Neurons / physiology* Patch-Clamp Techniques Phosphotransferases (Alcohol Group Acceptor) / genetics Phosphotransferases (Alcohol Group Acceptor) / metabolism* Protein Transport / drug effects Protein Transport / genetics RNA, Small Interfering Receptors, AMPA / genetics Receptors, AMPA / metabolism* Receptors, N-Methyl-D-Aspartate / metabolism Time Factors Transfection
IF 14.415
Times Cited 45
DNA material pGEX6P1- PIP5Kc661 Cterm-WT(434-661 a.a.) (RDB08477) pGEX6P1- PIP5Kc661 Cterm-SA(434-661 a.a.) (RDB08478) pGEX6P1- PIP5Kc661 Cterm-SE(434-661 a.a.) (RDB08479) pGEX6P1- PIP5Kc661 C26aa-SA(636-661 a.a.) (RDB08480) pGEX6P1- PIP5Kc661 C26aa-SE(636-661 a.a.) (RDB08481)