Journal Article

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

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

2013

Overview

SignificanceLong-term depression (LTD) commonly affects learning and memory in various brain regions. Although LTD in the cerebellum absolutely requires δ2 glutamate receptors, its underlying mechanisms remain elusive. LTD is caused by endocytosis of AMPA receptors, which is triggered by activity-induced serine phosphorylation of the GluA2 subunit. Our work showed that this serine phosphorylation required prior dephosphorylation of the nearby tyrosine residue. By interaction with a tyrosine phosphatase, δ2 glutamate receptors regulated tyrosine dephosphorylation status of GluA2 to gate inducibility of LTD. These findings will provide better understanding of general mechanisms regulating AMPA receptor endocytosis during synaptic plasticity. Long-term depression (LTD) commonly affects learning and memory in various brain regions. Although cerebellar LTD absolutely requires the δ2 glutamate receptor (GluD2) that is expressed in Purkinje cells, LTD in other brain regions does not; why and how cerebellar LTD is regulated by GluD2 remains unelucidated. Here, we show that the activity-dependent 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 GluA2 were 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.

• Publisher: National Academy of Sciences
• Subject: ADP-Ribosylation Factors - physiology / Animals / Biological Sciences / cerebellum / Cerebellum - physiology / dephosphorylation / endocytosis / glutamic acid / Guanine Nucleotide Exchange Factors - physiology / Long-Term Synaptic Depression - physiology / memory / Mice / Mice, Knockout / Models, Neurological / Neuronal Plasticity - physiology / Neuroscience / Patch-Clamp Techniques / Phosphorylation / PNAS Plus / PNAS Plus: SIGNIFICANCE STATEMENTS / Protein Interaction Domains and Motifs / Protein Subunits / Protein Tyrosine Phosphatase, Non-Receptor Type 4 - physiology / protein-tyrosine-phosphatase / Purkinje Cells - physiology / Receptors, AMPA - chemistry / Receptors, AMPA - genetics / Receptors, AMPA - physiology / Receptors, Glutamate - chemistry / Receptors, Glutamate - deficiency / Receptors, Glutamate - genetics / Receptors, Glutamate - physiology / serine / Serine - chemistry / Signal Transduction / tyrosine / Tyrosine - chemistry