Novel regulatory mechanism of anesthetic efficay by GABA-A receptor trafficking

• Project/Area Number: 15K10503
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Hirosaki University
• Principal Investigator: UENO Shinya 弘前大学, 医学研究科, 教授 (00312158)
• Co-Investigator(Kenkyū-buntansha): 尾崎 拓 弘前大学, 医学研究科, 特任助教 (70621069)
• Research Collaborator: FURUKAWA Tomonori 弘前大学, 大学院医学研究科, 助教 (60402369) ; NIKAIDOU Yoshikazu 弘前大学, 大学院医学研究科, 助教 (50613478) ; SHIMOYAMA Shuji 弘前大学, 大学院医学研究科, 助教 (60736370)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 麻酔作用調節 / GABA-A受容体トラフィッキング / 受容体リン酸化調節 / 麻酔薬 / GABA / 受容体トラフィッキング / 受容体リン酸化 / GABA-A受容体細胞内分布 / シナプス外GABA-A受容体 / ベンゾジアゼピン長期投与

Outline of Final Research Achievements

We showed that efficacy of anesthetics was regulated by GABA-A receptor trafficking via receptor phosphorylation. GABA-A receptor is the major target protein of anesthetics and distributed synaptic and extrasynaptic sites of plasma membrane. Disruption of trafficking of these receptors from synaptic to extrasynaptic sites caused to reduce the efficacy of anesthetics. Interesingly, this reduced effect was rescued in the presence of dephosphorylation inhibitor. These results indicated that the levels of phosphorylation in the receptor determined the efficacy of anesthetics, suggesting that efficacy of anesthetics is controlable even after administration of anesthetics.

Research Products

• [Journal Article] Morphological dendritic spine changes of medium spiny neurons in the nucleus accumbens in 6-hydroxydopamine-lesioned rats treated with levodopa. (2017)
  • Author(s): Funamizu Y, Nishijima H, Ueno T, Ueno S, Mizukami H, Yagihashi S, Tomiyama M.
  • Journal Title: Neurosci Res. Volume: 121 Pages: 49-53
  • DOI: 10.1016/j.neures.2017.03.010
  • Peer Reviewed / Open Access
• [Journal Article] Levodopa treatment and dendritic spine pathology. (2017)
  • Author(s): Nishijima H, Ueno T, Funamizu Y, Ueno S, Tomiyama M.
  • Journal Title: Mov Disord. Volume: 印刷中 Issue: 6 Pages: 877-888
  • DOI: 10.1002/mds.27172
  • Peer Reviewed / Open Access
• [Journal Article] Propofol anesthesia is reduced in Phospholipase C-related inactive protein type-1 knockout mice (2017)
  • Author(s): Nikaido Y, Furukawa T, Shimoyama S, Yamada J, Migita K, Koga K, Kushikata T, Hirota K, Kanematsu T, Hirata M, Ueno S
  • Journal Title: The Journal of pharmacology and experimental therapeutics Volume: 361(3) Issue: 3 Pages: 367-374
  • DOI: 10.1124/jpet.116.239145
  • Peer Reviewed / Open Access
• [Journal Article] Chronic diazepam administration increases the expression of Lcn2 in the CNS (2017)
  • Author(s): Tomonori Furukawa, Shuji Shimoyama, Yasuo Miki, Yoshikazu Nikaido, Kohei Koga, Kazuhiko Nakamura, Koichi Wakabayashi & Shinya Ueno
  • Journal Title: Pharmacology Research & Perspectives Volume: 5(1) Issue: 1 Pages: 1-12
  • DOI: 10.1002/prp2.283
  • NAID: 120006576912
  • Peer Reviewed / Open Access
• [Journal Article] Activations of muscarinic M1 receptors in the anterior cingulate cortex contribute to the antinociceptive effect via GABAergic transmission (2017)
  • Author(s): Kohei Koga, Yu Matsuzaki, Kenji Honda, Fumihiro Eto, Tomonori Furukawa, Keisuke Migita, Keiichi Irie, Kenichi Mishima and Shinya Ueno
  • Journal Title: Molecular Pain Volume: 13 Pages: 1-11
  • DOI: 10.1177/1744806917692330
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Spine enlargement of pyramidal tract-type neurons in the motor cortex of a rat model of levodopa-induced dyskinesia (2017)
  • Author(s): Tatsuya Ueno, Haruo Nishijima, Shinya Ueno and Masahiko Tomiyama
  • Journal Title: Frontiers in Neuroscience Volume: 11 Pages: 206-206
  • DOI: 10.3389/fnins.2017.00206
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Duloxetine increases the effects of levodopa in a rat model of Parkinson’s disease (2016)
  • Author(s): Haruo Nishijima, Tatsuya Ueno, Shinya Ueno and Masahiko Tomiyama
  • Journal Title: Neurology and Clinical Neurosci Volume: 4 Issue: 4 Pages: 129-133
  • DOI: 10.1111/ncn3.12051
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HSP90 Regulation of P2X7 Receptor Function Requires an Intact Cytoplasmic C-Terminus. (2016)
  • Author(s): Migita K, Ozaki T, Shimoyama S, Yamada J., Nikaido Y, Furukawa T, Shiba Y, Egan TM, Ueno S.
  • Journal Title: Molecular Pharmacology Volume: 90 (2) Issue: 2 Pages: 116-126
  • DOI: 10.1124/mol.115.102988
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] cis-3-Hexenol and trans-2-hexenal mixture prevents development of PTSD-like phenotype in rats. (2016)
  • Author(s): Yoshikazu Nikaido, Junko Yamada, Keisuke Migita, Yuko Shiba, Tomonori Furukawa, Toshihiro Nakashima, Shinya Ueno
  • Journal Title: Behavioural brain research Volume: 297 Pages: 251-258
  • DOI: 10.1016/j.bbr.2015.10.023
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Spontaneous epileptic seizures in transgenic rats harboring a human ADNFLE missense mutation in the β2-subunit of the nicotinic acetylcholine receptor. (2015)
  • Author(s): Yuko Shiba, Fumiaki Mori, Junko Yamada, Keisuke Migita, Yoshikazu Nikaido, Koichi Wakabayashi, Sunao Kaneko, Motohiro Okada, Shinichi Hirose, Shinya Ueno
  • Journal Title: Neuroscience research Volume: 100 Pages: 46-54
  • DOI: 10.1016/j.neures.2015.06.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] The effect of chronic diazepam administration on hippocampal long-term potentiation and spine morphology (2018)
  • Author(s): Tomonori Furukawa, Yoshikazu Nikaido, Shuji Shimoyama, Yoshiki Ogata, Kazuhiko Nakamura and Shinya Ueno
  • Organizer: 第95回日本生理学会大会
• [Presentation] The Association Between Anxiety and Motor Function Recovery After Spinal Cord Injury In Gabaa Receptor-defective Mice (2018)
  • Author(s): TAKU FUJITA; Gentaro Kumagai; Xizhe Liu; Hitoshi Kudo; Toru Asari; Yoshikazu Nikaido; Shinya Ueno; Yasuyuki Ishibashi
  • Organizer: ORS 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] Chronic diazepam administration increases the expression of Lcn2 in the CNS (2017)
  • Author(s): Tomonori Furukawa, Shuji Shimoyama, Yasuo Miki, Yoshikazu Nikaido, Kohei Koga, Kazuhiko Nakamura, Koichi Wakabayashi, and Shinya Ueno
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松(浜松市）
  • Year and Date: 2017-03-28
• [Presentation] Chronic diazepam administration impairs acquisition of spatial reference memory in aged mice (2017)
  • Author(s): Yoshikazu Nikaido, Tomonori Furukawa, Shuji Shimoyam, Kohei Koga, and Shinya Ueno
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松(浜松市）
  • Year and Date: 2017-03-28
• [Presentation] The effect of chronic diazepam administration on Lcn2 expression and spine morphology (2017)
  • Author(s): Tomonori Furukawa, Shuji Shimoyama, Yoshikazu Nikaido, Yasuo Miki, Kohei Koga, Kazuhiko Nakamura, Koichi Wakabayashi, and Shinya Ueno
  • Organizer: 第40回神経科学学会
• [Presentation] AP-1 complex induces mouse Tspo gene expression by lipopolysaccharide in microglial cell line, BV-2 (2017)
  • Author(s): Shuji Shimoyama, Tomonori Furukawa, Yoshiki Ogata, Shinya Ueno and Kazuhiko Nakamura
  • Organizer: 第44回日本脳科学会
• [Presentation] The effect of chronic diazepam administration induced upregulation of Lcn2 expression on cognitive function (2017)
  • Author(s): Yoshiki Ogata, Tomonori Furukawa, Yoshikazu Nikaido, Shuji Shimoyama, Kazuhiko Nakamura and Shinya Ueno
  • Organizer: 第44回日本脳科学会
• [Presentation] Phospholipase C-related inactive protein type-1 deficiency alters anesthetic electroencephalogram induced by propofol in mice (2017)
  • Author(s): Yoshikazu Nikaido, Tomonori Furukawa, Shuji Shimoyama, Tetsuya Kushikata, Kazuyoshi Hirota, Takashi Kanematsu, Masato Hirata and Shinya Ueno
  • Organizer: 第40回神経科学学会
• [Presentation] 慢性社会的敗北ストレスによってうつ病様モデル化したラットは前頭前野の機能異常を起こす (2017)
  • Author(s): 二階堂義和, 古川智範, 下山修司, 櫛方哲也, 廣田和美, 上野伸哉
  • Organizer: 第44回日本脳科学会
• [Presentation] 遺伝子Tspo の発現調節メカニズムの解明 (2016)
  • Author(s): 下山修司、中村和彦、上野伸哉
  • Organizer: 日本生化学会 東北支部 第82 回例会・シンポジウム
  • Place of Presentation: 弘前大学(弘前市）
  • Year and Date: 2016-05-21
• [Presentation] 社会ストレスは認知脳低下を来す (2016)
  • Author(s): 二階堂義, 古川智範, 古賀浩平, 上野伸哉
  • Organizer: 第93回 日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Year and Date: 2016-03-22
• [Presentation] ラット前帯状皮質は恐怖記憶の想起と消去では左右異なる活動を示す (2016)
  • Author(s): 古川智範、二階堂義和、右田啓介、下山修司、尾崎拓、古賀浩平、上野伸哉
  • Organizer: 第93回 日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Year and Date: 2016-03-22
• [Presentation] 麻酔科医が知っておくべき中枢神経系受容体:GABA-A受容体トラフィッキングによる麻酔効果制御 (2015)
  • Author(s): 上野伸哉
  • Organizer: 日本麻酔学会 第62回学術集会
  • Place of Presentation: 神戸ポートピアホテル（神戸市）
  • Year and Date: 2015-05-28
  • Invited