title: The δ2 glutamate receptor gates long-term depression by coordinating interactions between two AMPA receptor phosphorylation sites.
abstract: 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.
authors: Department of Physiology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
authors: Kazuhisa
authors: K
authors: Kohda
authors: Wataru
authors: W
authors: Kakegawa
authors: Shinji
authors: S
authors: Matsuda
authors: Tadashi
authors: T
authors: Yamamoto
authors: Hisashi
authors: H
authors: Hirano
authors: Michisuke
authors: M
authors: Yuzaki
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000502:physiology; D000818:Animals; D002531:Cerebellum / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D021122:Protein Subunits; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4 / Q000502:physiology; D011689:Purkinje Cells / Q000502:physiology; D018091:Receptors, AMPA / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017470:Receptors, Glutamate / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry
chemical_list: D000089982:ADP-Ribosylation Factor 6; D020662:Guanine Nucleotide Exchange Factors; D021122:Protein Subunits; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2; D014443:Tyrosine; D012694:Serine; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4; D020727:ADP-Ribosylation Factors; C104722:glutamate receptor ionotropic, AMPA 2