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Study of regulatory system for anesthetic efficacy using GABA-A receptor plasticity

Research Project

Project/Area Number 18K08846
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 55050:Anesthesiology-related
Research InstitutionHirosaki University

Principal Investigator

UENO Shinya  弘前大学, 医学研究科, 教授 (00312158)

Co-Investigator(Kenkyū-buntansha) 古川 智範  弘前大学, 医学研究科, 助教 (60402369)
櫛方 哲也  弘前大学, 医学研究科, 准教授 (80250603)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsGABA-A受容体 / 麻酔薬 / 受容体トラフィッキング / 受容体リン酸化変異 / 受容体リン酸化 / GABA-A受容体 / :受容体リン酸化
Outline of Final Research Achievements

We investigated the mechanism of GABA-A receptor trafficking through subunit phosphorylation. Control and mutation-induced cell lines were established using Neuro2A strain. These cell lines stably co-express three kinds of subunits, alpha-, beta3-, and gamma. HA-tag inserted in beta3 subunit introduced the visualization of GABA-A distribution. Confocal microscopy analysis revealed that mutation of phyosphorylation sites of beta3 subunit caused to disturb the trafficking of GABA-A receptors from intracellular region to plasma membrane. Consequently, GABA-induced current in cell lines with mutated beta3 subunit decreased under patch-clamp recordings. These results suggest that phyosphorylation of GABA-A receptor regulate the efficacy of anesthetics with the enhancing effect on GABA.

Academic Significance and Societal Importance of the Research Achievements

吸入麻酔薬や静脈麻酔薬において全身麻酔効果発現にGABA応答の増強効果が認められている。GABA応答はGABA-A受容体を介しており、本研究結果からGABA-A受容体の応答がリン酸化調節によって可逆的に制御可能であることが示唆された。既に存在するGABA-A受容体増強作用をもつ麻酔薬の効果に対して、新たな調節機構を明らかとした。また、薬物代謝障害による麻酔薬の遷延などを、薬物投与後であっても反応進展を止める、いわゆる"麻酔状態からのリバース"を薬物種に依存せず可能とし、副作用発現の予防にも有効な手段となりうる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (21 results)

All 2021 2020 2019 2018 Other

All Journal Article (11 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 9 results) Presentation (9 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Copy number variations in Japanese children with autism spectrum disorder2021

    • Author(s)
      Sakamoto, Yui; Shimoyama, Shuji; Furukawa, Tomonori; Adachi, Masaki; Takahashi, Michio; Mikami, Tamaki; Kuribayashi, Michito; Osato, Ayako; Tsushima, Daiki; Saito, Manabu; Ueno, Shinya; Nakamura, Kazuhiko
    • Journal Title

      Psychiatric Genetics

      Volume: - Issue: 3 Pages: 276-276

    • DOI

      10.1097/ypg.0000000000000276

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Sex-Related Differences in Anxiety and Functional Recovery after Spinal Cord Injury in Mice2020

    • Author(s)
      Fukutoku Tatsuhiro、Kumagai Gentaro、Fujita Taku、Sasaki Ayako、Wada Kanichiro、Liu Xizhe、Tanaka Toshihiro、Kudo Hitoshi、Asari Toru、Nikaido Yoshikazu、Ueno Shinya、Ishibashi Yasuyuki
    • Journal Title

      Journal of Neurotrauma

      Volume: 37 Issue: 21 Pages: 2235-2243

    • DOI

      10.1089/neu.2019.6929

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming2020

    • Author(s)
      Nishijima H, Mori F, Arai A, Zhu G, Wakabayashi K, Okada M, Ueno S, Ichinohe N, Suzuki C, Kon T, Tomiyama M
    • Journal Title

      Neurobiol Dis

      Volume: 143 Pages: 104979-104979

    • DOI

      10.1016/j.nbd.2020.104979

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor2020

    • Author(s)
      Yabuki Yasushi、Liu Jiaqi、Kawahata Ichiro、Izumi Hisanao、Shinoda Yasuharu、Koga Kohei、Ueno Shinya、Shioda Norifumi、Fukunaga Kohji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 15 Pages: 5525-5525

    • DOI

      10.3390/ijms21155525

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Triphenyltin disrupts intracellular Zn2+ homeostasis in rat thymic lymphocytes2020

    • Author(s)
      Ueno Toshiya、Oyama Keisuke、Hyung Youn Jae、Ueno Shinya、Oyama Yasuo
    • Journal Title

      Toxicology in Vitro

      Volume: 65 Pages: 104782-104782

    • DOI

      10.1016/j.tiv.2020.104782

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lipopolysaccharide induces mouse translocator protein (18 kDa) expression via the AP-1 complex in the microglial cell line, BV-22019

    • Author(s)
      Shimoyama Shuji、Furukawa Tomonori、Ogata Yoshiki、Nikaido Yoshikazu、Koga Kohei、Sakamoto Yui、Ueno Shinya、Nakamura Kazuhiko
    • Journal Title

      PLOS ONE

      Volume: 14 Issue: 9 Pages: 1-15

    • DOI

      10.1371/journal.pone.0222861

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phospholipase C-related inactive protein type-1 deficiency affects anesthetic electroencephalogram activity induced by propofol and etomidate in mice2019

    • Author(s)
      Furukawa Tomonori、Nikaido Yoshikazu、Shimoyama Shuji、Ogata Yoshiki、Kushikata Tetsuya、Hirota Kazuyoshi、Kanematsu Takashi、Hirata Masato、Ueno Shinya
    • Journal Title

      Journal of Anesthesia

      Volume: 33 Issue: 4 Pages: 531-542

    • DOI

      10.1007/s00540-019-02663-z

    • NAID

      40021971791

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-hypersensitive effect of angiotensin (1-7) on streptozotocin-induced diabetic neuropathic pain in mice2019

    • Author(s)
      Yoshiki Ogata, Wataru Nemoto, Ryota Yamagata, Osamu Nakagawasai, Shuji Shimoyama, Tomonori Furukawa, Shinya Ueno, Koichi Tan-No
    • Journal Title

      Eur. J. Pain

      Volume: 23 Issue: 4 Pages: 739-749

    • DOI

      10.1002/ejp.1341

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Zonisamide Enhances Motor Effects of Levodopa, Not of Apomorphine, in a Rat Model of Parkinson’s Disease2018

    • Author(s)
      Nishijima Haruo、Miki Yasuo、Ueno Shinya、Tomiyama Masahiko
    • Journal Title

      Parkinson's Disease

      Volume: 2018 Pages: 1-7

    • DOI

      10.1155/2018/8626783

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Poor motor-function recovery after spinal-cord injury in anxiety-model mice with phospholipase related catalytically inactive protein type 1 knockout.2018

    • Author(s)
      Taka Fujita, Gentaro Kumagai, Xizhe Liu, Kanichiro Wada, Toshihiro Tanaka, Hitoshi Kudo, Toru Asari, Tatsuhiro Fukutoku, Ayako Sasaki, Yohshiro Nitobe, Yoshikazu Nikaido, Ken-Ichi Furukawa, Masato Hirata, Takashi Kanematsu, Shinya Ueno, Yasuyuki Ishibash
    • Journal Title

      Journal of Neurotrauma

      Volume: 印刷中 Issue: 12 Pages: 1379-1386

    • DOI

      10.1089/neu.2017.5492

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chronic inflammatory pain induced GABAergic synaptic plasticity in the adult mouse anterior cingulate cortex2018

    • Author(s)
      Koga Kohei、Shimoyama Shuji、Yamada Akihiro、Furukawa Tomonori、Nikaido Yoshikazu、Furue Hidemasa、Nakamura Kazuhiko、Ueno Shinya
    • Journal Title

      Molecular Pain

      Volume: 14 Pages: 1-14

    • DOI

      10.1177/1744806918783478

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] The effect of chronic diazepam administration on hippocampus of aged mice. (演題名)抗不安薬ジアゼパム慢性投与の海馬機能への影響2021

    • Author(s)
      T. Furukawa, Y. Nikaido, S. Shimoyama, S. Ueno
    • Organizer
      第98回日本生理学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 抗不安薬ジアゼパムの長期使用による海馬神経機能への影響2020

    • Author(s)
      古川智範、二階堂義和、下山修司、上野伸哉
    • Organizer
      第47回日本脳科学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Lcn2のジアゼパムによる遺伝子発現調節機構2020

    • Author(s)
      下山 修司, 古川 智範 , 上野 伸哉
    • Organizer
      第43回日本神経科学学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 老齢マウスにおけるジアゼパム慢性投与の認知機能に及ぼす影響2020

    • Author(s)
      古川 智範, 二階堂 義和, 下山 修司, 小潟 佳輝, 上野 伸哉
    • Organizer
      第43回日本神経科学学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] PropofolおよびEtomidateの麻酔脳波におけるPRIP-1欠損の影響2020

    • Author(s)
      T. Furukawa, Y. Nikaido, S.Shimoyama, Y.Ogata, T. Kushikata, K. Hirota, T.Kanematsu, M. Hirata, S.Ueno
    • Organizer
      弘前メディカルフォーラム
    • Related Report
      2019 Research-status Report
  • [Presentation] Chronic diazepam administration impaired hippocampal CA3 LTP and spine morphology in aged mice2020

    • Author(s)
      T. Furukawa, Y. Nikaido, S. Shimoyama, Y. Ogata, and S. Ueno
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] The effect of benzodiazepine on proliferation and survivals of CNS cells2019

    • Author(s)
      T. Furukawa, S. Shimoyama, Y. Ogata, and S. Ueno
    • Organizer
      第96回日本生理学会大会 第9回アジア・オセアニア生理学会連合2019年大会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Phospholipase C-related inactive protein type-1 deficiency alters propofol-induced EEG activity2019

    • Author(s)
      Y Nikaido, T Furukawa, S Shimoyama, Y Ogata, T Kushikata, K Hirota, M Hirata, T Kanematsu, S Ueno
    • Organizer
      第96回日本生理学会大会 第9回アジア・オセアニア生理学会連合2019年大会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 動物モデルにおける糖尿病性 疼痛の解析2019

    • Author(s)
      上野伸哉
    • Organizer
      第53回糖尿病学の進歩
    • Related Report
      2018 Research-status Report
    • Invited
  • [Remarks] 弘前大学 大学院医学研究科 脳神経生理学講座

    • URL

      http://www.med.hirosaki-u.ac.jp/~neurophysiol/

    • Related Report
      2019 Research-status Report

URL: 

Published: 2018-04-23   Modified: 2022-01-27  

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