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 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.
| Original language | English |
|---|---|
| Pages (from-to) | 135-148 |
| Number of pages | 14 |
| Journal | Neuron |
| Volume | 73 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2012 Jan 12 |
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ASJC Scopus subject areas
- Neuroscience(all)
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NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P 2 Is Essential for AMPA Receptor Endocytosis during LTD. / Unoki, Takamitsu; Matsuda, Shinji; Kakegawa, Wataru; Van, Ngo Thai Bich; Kohda, Kazuhisa; Suzuki, Atsushi; Funakoshi, Yuji; Hasegawa, Hiroshi; Yuzaki, Michisuke; Kanaho, Yasunori.
In: Neuron, Vol. 73, No. 1, 12.01.2012, p. 135-148.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P 2 Is Essential for AMPA Receptor Endocytosis during LTD
AU - Unoki, Takamitsu
AU - Matsuda, Shinji
AU - Kakegawa, Wataru
AU - Van, Ngo Thai Bich
AU - Kohda, Kazuhisa
AU - Suzuki, Atsushi
AU - Funakoshi, Yuji
AU - Hasegawa, Hiroshi
AU - Yuzaki, Michisuke
AU - Kanaho, Yasunori
PY - 2012/1/12
Y1 - 2012/1/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84855755558&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2011.09.034
DO - 10.1016/j.neuron.2011.09.034
M3 - Article
C2 - 22243752
AN - SCOPUS:84855755558
VL - 73
SP - 135
EP - 148
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 1
ER -