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

作者：Unoki Takamitsu; Matsuda Shinji; Kakegawa Wataru; Ngo Thai Bich Van; Kohda Kazuhisa; Suzuki Atsushi; Funakoshi Yuji; Hasegawa Hiroshi; Yuzaki Michisuke^*; Kanaho Yasunori

来源：Neuron, 2012, 73(1): 135-148.

DOI：10.1016/j.neuron.2011.09.034

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-kinase gamma 661 (PIP5K gamma 661), the major phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2)-producing enzyme in the brain. Bimolecular fluorescence complementation analysis revealed that the dephosphorylated PIP5K gamma 661 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 PIP5K gamma 661 and AP-2 and by overexpression of a kinase-dead PIP5K gamma 661 mutant in hippocampal neurons. Furthermore, knockdown of PIP5K gamma 661 inhibited the NMDA-induced AMPA receptor endocytosis. Therefore, NMDA receptor activation controls AMPA receptor endocytosis during hippocampal LTD by regulating PIP5K gamma 661 activity at postsynapses.

• 出版日期2012-1-12