1. NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P2 Is Essential for AMPA Receptor Endocytosis during LTD
- Author
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Michisuke Yuzaki, Yasunori Kanaho, Takamitsu Unoki, Yuji Funakoshi, Wataru Kakegawa, Ngo Thai Bich Van, Atsushi Suzuki, Shinji Matsuda, Hiroshi Hasegawa, and Kazuhisa Kohda
- Subjects
biology ,Chemistry ,Neuroscience(all) ,General Neuroscience ,AMPA receptor ,Endocytosis ,Clathrin ,Cell biology ,chemistry.chemical_compound ,nervous system ,Disks Large Homolog 4 Protein ,biology.protein ,NMDA receptor ,Phosphatidylinositol ,Receptor ,Long-term depression - Abstract
SummaryNMDA 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.
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