NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P 2 Is Essential for AMPA Receptor Endocytosis during LTD

Takamitsu Unoki, Shinji Matsuda, Wataru Kakegawa, Ngo Thai Bich Van, Kazuhisa Kohda, Atsushi Suzuki, Yuji Funakoshi, Hiroshi Hasegawa, Michisuke Yuzaki, Yasunori Kanaho

研究成果: Article査読

50 被引用数 (Scopus)

抄録

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 Ca 2+ 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)P 2)-producing enzyme in the brain. Bimolecular fluorescence complementation analysis revealed that the dephosphorylated PIP5Kγ661 became associated with the clathrin adaptor protein complex AP-2 atpostsynapses insitu. 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 ofa 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. AMPA receptor endocytosis is essential for LTD induction, but it is not clear how this process is controlled. Unoki etal. find that NMDA receptor activation controls AMPA receptor endocytosis during hippocampal LTD by regulating the activity of the enzyme PIP5Kγ661.

本文言語English
ページ(範囲)135-148
ページ数14
ジャーナルNeuron
73
1
DOI
出版ステータスPublished - 2012 1 12

ASJC Scopus subject areas

  • Neuroscience(all)

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