title: Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour.
abstract: Major depressive and bipolar disorders are serious illnesses that affect millions of people. Growing evidence implicates glutamate signalling in depression, though the molecular mechanism by which glutamate signalling regulates depression-related behaviour remains unknown. In this study, we provide evidence suggesting that tyrosine phosphorylation of the NMDA receptor, an ionotropic glutamate receptor, contributes to depression-related behaviour. The NR2A subunit of the NMDA receptor is tyrosine-phosphorylated, with Tyr 1325 as its one of the major phosphorylation site. We have generated mice expressing mutant NR2A with a Tyr-1325-Phe mutation to prevent the phosphorylation of this site in vivo. The homozygous knock-in mice show antidepressant-like behaviour in the tail suspension test and in the forced swim test. In the striatum of the knock-in mice, DARPP-32 phosphorylation at Thr 34, which is important for the regulation of depression-related behaviour, is increased. We also show that the Tyr 1325 phosphorylation site is required for Src-induced potentiation of the NMDA receptor channel in the striatum. These data argue that Tyr 1325 phosphorylation regulates NMDA receptor channel properties and the NMDA receptor-mediated downstream signalling to modulate depression-related behaviour.
authors.affiliation: Division of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Asami
authors.initials: A
authors.lastname: Tanimura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kiyama
authors.forename: Tohru
authors.initials: T
authors.lastname: Tezuka
authors.forename: Ayako M
authors.initials: AM
authors.lastname: Watabe
authors.forename: Norikazu
authors.initials: N
authors.lastname: Katayama
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kakuta
authors.forename: Katsuko
authors.initials: K
authors.lastname: Sudo
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Hisashi
authors.initials: H
authors.lastname: Umemori
authors.forename: Takafumi
authors.initials: T
authors.lastname: Inoue
authors.forename: Niall P
authors.initials: NP
authors.lastname: Murphy
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
authors.forename: Toshiya
authors.initials: T
authors.lastname: Manabe
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002460:Cell Line; D003863:Depression / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010649:Phenylalanine / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000235:genetics / Q000502:physiology*
chemical_list: D010649:Phenylalanine; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine