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

Research output: Contribution to journalArticle

48 Citations (Scopus)

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 languageEnglish
Pages (from-to)135-148
Number of pages14
JournalNeuron
Volume73
Issue number1
DOIs
Publication statusPublished - 2012 Jan 12

Fingerprint

AMPA Receptors
Endocytosis
N-Methyl-D-Aspartate Receptors
N-Methylaspartate
Adaptor Protein Complex 2
Protein Phosphatase 1
Clathrin
Enzymes
Phosphatidylinositols
phosphatidylinositol 4-phosphate
Hippocampus
Fluorescence
Neurons
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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 journalArticle

Unoki, T, Matsuda, S, Kakegawa, W, Van, NTB, Kohda, K, Suzuki, A, Funakoshi, Y, Hasegawa, H, Yuzaki, M & Kanaho, Y 2012, 'NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P 2 Is Essential for AMPA Receptor Endocytosis during LTD', Neuron, vol. 73, no. 1, pp. 135-148. https://doi.org/10.1016/j.neuron.2011.09.034
Unoki, Takamitsu ; Matsuda, Shinji ; Kakegawa, Wataru ; Van, Ngo Thai Bich ; Kohda, Kazuhisa ; Suzuki, Atsushi ; Funakoshi, Yuji ; Hasegawa, Hiroshi ; Yuzaki, Michisuke ; Kanaho, Yasunori. / NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P 2 Is Essential for AMPA Receptor Endocytosis during LTD. In: Neuron. 2012 ; Vol. 73, No. 1. pp. 135-148.
@article{61d342f845df4849943d17bbb603e8ec,
title = "NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P 2 Is Essential for AMPA Receptor Endocytosis during LTD",
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.",
author = "Takamitsu Unoki and Shinji Matsuda and Wataru Kakegawa and Van, {Ngo Thai Bich} and Kazuhisa Kohda and Atsushi Suzuki and Yuji Funakoshi and Hiroshi Hasegawa and Michisuke Yuzaki and Yasunori Kanaho",
year = "2012",
month = "1",
day = "12",
doi = "10.1016/j.neuron.2011.09.034",
language = "English",
volume = "73",
pages = "135--148",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84855755558&partnerID=8YFLogxK

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 -