NMDA receptor-mediated PIP5K activation to produce PI(4,5)P₂ is essential for AMPA receptor endocytosis during LTD

Neuron. 2012 Jan 12;73(1):135-48. doi: 10.1016/j.neuron.2011.09.034.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Actins
  • Adaptor Protein Complex 2
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Membrane Proteins
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Green Fluorescent Proteins
  • N-Methylaspartate
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • Guanylate Kinases
  • glutamate receptor ionotropic, AMPA 2