The δ2 glutamate receptor gates long-term depression by coordinating interactions between two AMPA receptor phosphorylation sites

Kazuhisa Kohda, Wataru Kakegawa, Shinji Matsuda, Tadashi Yamamoto, Hisashi Hirano, Michisuke Yuzaki

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34 Citations (Scopus)

Abstract

Long-term depression (LTD) commonly affects learning andmemoryin various brain regions. Although cerebellar LTD absolutely requires the δ2 glutamate receptor (GluD2) that is expressed in Purkinje cells, LTDin other brain regions does not;why andhowcerebellar LTD is regulated by GluD2 remains unelucidated. Here, we show that the activitydependent phosphorylation of serine 880 (S880) in GluA2 AMPA receptor subunit, which is an essential step for AMPA receptor endocytosis during LTD induction, was impaired in GluD2-null cerebellum. In contrast, the basal phosphorylation levels of tyrosine 876 (Y876) in GluA2were increased in GluD2-null cerebellum. An in vitro phosphorylation assay revealed that Y876 phosphorylation inhibited subsequent S880 phosphorylation. Conversely, Y876 dephosphorylation was sufficient to restore S880 phosphorylation and LTD induction in GluD2-null Purkinje cells. Furthermore, megakaryocyte protein tyrosine phosphatase (PTPMEG), which binds to the C terminus of GluD2, directly dephosphorylated Y876. These data indicate that GluD2 gates LTD by coordinating interactions between the two phosphorylation sites of the GluA2.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number10
DOIs
Publication statusPublished - 2013 Mar 5

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AMPA Receptors
Glutamate Receptors
Phosphorylation
Depression
Serine
Purkinje Cells
Cerebellum
Null Lymphocytes
Protein Tyrosine Phosphatases
Megakaryocytes
Brain
Endocytosis
Tyrosine
Learning

Keywords

  • Mouse
  • Synaptic plasticity

ASJC Scopus subject areas

  • General

Cite this

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AU - Kakegawa, Wataru

AU - Matsuda, Shinji

AU - Yamamoto, Tadashi

AU - Hirano, Hisashi

AU - Yuzaki, Michisuke

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N2 - Long-term depression (LTD) commonly affects learning andmemoryin various brain regions. Although cerebellar LTD absolutely requires the δ2 glutamate receptor (GluD2) that is expressed in Purkinje cells, LTDin other brain regions does not;why andhowcerebellar LTD is regulated by GluD2 remains unelucidated. Here, we show that the activitydependent phosphorylation of serine 880 (S880) in GluA2 AMPA receptor subunit, which is an essential step for AMPA receptor endocytosis during LTD induction, was impaired in GluD2-null cerebellum. In contrast, the basal phosphorylation levels of tyrosine 876 (Y876) in GluA2were increased in GluD2-null cerebellum. An in vitro phosphorylation assay revealed that Y876 phosphorylation inhibited subsequent S880 phosphorylation. Conversely, Y876 dephosphorylation was sufficient to restore S880 phosphorylation and LTD induction in GluD2-null Purkinje cells. Furthermore, megakaryocyte protein tyrosine phosphatase (PTPMEG), which binds to the C terminus of GluD2, directly dephosphorylated Y876. These data indicate that GluD2 gates LTD by coordinating interactions between the two phosphorylation sites of the GluA2.

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