Roles of Girdin in synaptic plasticity and memory

• Project/Area Number: 24390095
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: ASAI Naoya 名古屋大学, 医学(系)研究科(研究院), 准教授 (80273233)
• Co-Investigator(Kenkyū-buntansha): NAGAI Taku 名古屋大学, 医学部附属病院, 准教授 (10377426)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2013: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 記憶障害 / シナプス可塑性 / 蛋白リン酸化 / 疾患モデルマウス / BDNF/TekB/Akiシグナル / 海馬神経 / 蛋白リン酸 / アクチン結合蛋白 / 行動解析

Outline of Final Research Achievements

Girdin, an actin-binding protein involved both in the remodeling of the actin cytoskeleton and in cell migration, has been identified as a substrate of Akt at Girdin S1416. We focused on the role of Girdin S1416 phosphorylation in BDNF/TrkB/Akt signaling associated with synaptic plasticity. We found that Girdin in the hippocampus was phosphorylated at S1416 in an activity-dependent manner. Phosphorylation-deficient knock-in mice exhibited shrinkage of spines, deficit of hippocampal long-term potentiation, and memory impairment. Furthermore, Girdin interacted with Src kinase and NR2B subunit of NMDA receptor, leading to phosphorylation of the NR2B subunit and NMDA receptor activation. Our findings suggest that Girdin controls Akt-dependent NR2B phosphorylation through the interaction with Src, which is associated with synaptic plasticity in the hippocampus underlying memory formation.

Research Products

• [Journal Article] Akt-girdin signaling in cancer-associated fibroblasts contributes to tumor progression (2015)
  • Author(s): Yumiko Yamamura, Naoya Asai, Atsushi Enomoto, Takuya Kato, Shinji Mii, Yuji Kondo, Kaori Ushida, Kaoru Niimi, Nobuyuki Tsunoda, Masato Nagino, Shu Ichihara, Koichi Furukawa, Kengo Maeda, Toyoaki Murohara, Masahide Takahashi
  • Journal Title: Cancer Res, Volume: 75 Pages: 813-23
  • DOI: 10.1158/0008-5472.can-14-1317
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Girdin is phosphorylated on tyrosine 1798 when associated with structures required for migration (2015)
  • Author(s): Kenji Omori, Masato Asai, Daisuke Kuga, Kaori Ushida, Tetsuya Izuchi, Shinji Mii, Atsushi Enomoto, Naoya Asai, Masato Nagino, Masahide Takahashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 458 Pages: 934-40
  • DOI: 10.1016/j.bbrc.2015.02.065
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Girdin phosphorylation is crucial for synaptic plasticity and memory: A potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor (2014)
  • Author(s): Tsuyoshi Nakai, Taku Nagai, Motoki Tanaka, Norimichi Itoh, Naoya Asai, Atsushi Enomoto, Masato Asai, Shinnnosuke Yamada, Ali Bin Saifullah, Masahiro Sokabe, Masahide Takahashi, Kiyofumi Yamada
  • Journal Title: J. Neurosci. Volume: 34 Pages: 14995-15008
  • DOI: 10.1523/jneurosci.2228-14.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA (2014)
  • Author(s): Haruko Ota, Takao Hikita, Masato Sawada, Tomoki Nishioka, Mami Matsumoto, Masayuki Komura, Akihisa Ohno, Yukiyo Kamiya, Takuya Miyamoto, Naoya Asai, Atsushi Enomoto, Masahide Takahashi, Kozo Kaibuchi, Kazuya Sobue, Kazunobu Sawamoto
  • Journal Title: Nat. Commun. Volume: 5 Pages: 4532-4532
  • DOI: 10.1038/ncomms5532
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulation of cargo-selective endocytosis by dynamin 2 GTPase-activating protein girdin. (2014)
  • Author(s): Liang Weng, Atsushi Enomoto, Hiroshi Miyoshi, Kiyofumi Takahashi, Naoya Asai, Nobuhiro Morone, Ping Jiang, Jian An, Takuya Kato, Keisuke Kuroda, Takashi Watanabe, Masato Asai, Maki Ishida-Takagishi, Yoshiki Murakumo, Hideki Nakashima, Kozo Kaibuchi and Masahide Takahashi.
  • Journal Title: EMBO Journal Volume: 33 Pages: 2098-112
  • DOI: 10.15252/embj.201488289
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of Girdin in intimal hyperplasia in vein grafts and efficacy of atelocollagen-mediated application of siRNA for vein failure (2014)
  • Author(s): Hiroki Miyachi, Shinji Mii, Atsushi Enomoto, Yoshiki Murakumo, Takuya Kato, Naoya Asai, Kimihiro Komori, Masahide Takahashi
  • Journal Title: J Vasc Surg Volume: 60 Pages: 479-489
  • DOI: 10.1016/j.jvs.2013.06.080
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proteomic analysis of Girdin-interacting proteins in migrating new neurons in the postnatal mouse brain (2013)
  • Author(s): Haruko Ota, Takao Hikita, Tomoki Nishioka, Mami Matsumoto, Jun Ito, Naoya Asai, Atsushi Enomoto, Masahide Takahashi, Kozo Kaibuchi, Kazuya Sobue, Kazunobu Sawamoto
  • Journal Title: Biochem Biophys Res Commun. Volume: 442 Pages: 16-21
  • DOI: 10.1016/j.bbrc.2013.10.126
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Girdin and its phosphorylation dynamically regulate neonatal vascular development and pathological neovascularization in the retina (2013)
  • Author(s): Takanori Ito, Keiichi Komeima, Tetsuhiro Yasuma, Atsushi Enomoto, Naoya Asai, Masato Asai, Sayoko Iwase, Masahide Takahashi, Hiroko Terasaki
  • Journal Title: Am J Pathol Volume: 182 Pages: 586-596
  • DOI: 10.1016/j.ajpath.2012.10.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Similar phenotypes of Girdin germ-line and conditional knockout mice indicate a crucial role for Girdin in the nestin lineage (2012)
  • Author(s): Masato Asai
  • Journal Title: Biochem Biophys Res Commun Volume: 426 Pages: 533-538
  • DOI: 10.1016/j.bbrc.2012.08.122
  • Peer Reviewed
• [Journal Article] Involvement of Girdin in the determination of cell polarity during cell migration (2012)
  • Author(s): Ohara K, Enomoto A, et al.
  • Journal Title: PloS One Volume: 7
  • DOI: 10.1371/journal.pone.0036681
  • Peer Reviewed
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/patho2/