Regulation of Cerebellar Function by Redox Modification of Calcium-Release Channel

• Project/Area Number: 15K06774
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Kyoto University
• Principal Investigator: Kakizawa Sho 京都大学, 薬学研究科, 准教授 (40291059)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 一酸化窒素 / 活性酸素 / レドックスシグナル / 翻訳後修飾 / カルシウム放出 / リアノジン受容体 / 小脳 / 運動学習 / カルシウム / シナプス / 長期増強 / 記憶学習 / シナプス可塑性 / プルキンエ細胞

Outline of Final Research Achievements

Although possible involvement of redox signals, such as nitric oxide (NO) and reactive oxygen species (ROS), in brain functions are suggested in recent studies, the molecular mechanism and functional role of redox modification has yet to be determined. In the present study, we conducted knock-in (KI) mice expressing type 1 ryanodine receptor, a Ca2+ release channel, with Cys-to-Ala mutation. In this mice, NO-dependent S-nitrosylation of RyR1 was inhibited. In addition, cerebellar synaptic plasticity as well as cerebellar-dependent motor learning were also impaired. There results demonstrated that essential role of S-nitrosylation of RyR1 in learning and memory. Furthermore, pretreatment of the cerebellar slices with ROS abolished S-nitrosylation of RyR1 and the resultant activation of the receptor. Taken together, the study proceeds our understanding of biological significance and mode of action of redox signals in brain.

Academic Significance and Societal Importance of the Research Achievements

一酸化窒素(NO)や活性酸素(ROS)などのレドックスシグナルは、従来、生活習慣病や老化の主要因の一つとされ、悪玉的役割が注目されてきた。本研究ではNOによるCa2+放出チャネルの化学修飾(S-ニトロシル化)の小脳依存的運動学習への関与が解明され、レドックスシグナルの脳における善玉的作用が示された。これは悪玉因子とされていたレドックスシグナルが善玉的役割をも有することを示す、新規概念の提唱へと繋がる。
また、従来よりROSによる生体機能阻害が知られていたが、その分子機構は多くの点で不明であった。今回、ROSによるS-ニトロシル化阻害を介した生体機能阻害が示され、老化の分子機構の一端が解明された。

Research Products

• [Journal Article] TRPM7 channels mediate spontaneous Ca2+ fluctuations in growth plate chondrocytes that promote bone development. (2019)
  • Author(s): Qian N, Ichimura A, Takei D, Sakaguchi R, Kitani A, Nagaoka R, Tomizawa M, Miyazaki Y, Miyachi H, Numata T, Kakizawa S, Nishi M, Mori Y, Takeshima H.
  • Journal Title: Science signaling Volume: 12 Issue: 576 Pages: 4847-4847
  • DOI: 10.1126/scisignal.aaw4847
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Physiological roles of redox signals in relation to synaptic plasticity and brain functions (2018)
  • Author(s): Kakizawa Sho
  • Journal Title: Folia Pharmacologica Japonica Volume: 152 Issue: 5 Pages: 227-232
  • DOI: 10.1254/fpj.152.227
  • NAID: 130007503088
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Functional roles of phosphotyrosine adaptor Shc in the brain (2018)
  • Author(s): Kakizawa Sho
  • Journal Title: Folia Pharmacologica Japonica Volume: 152 Issue: 2 Pages: 84-89
  • DOI: 10.1254/fpj.152.84
  • NAID: 130007432230
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] ホスホチロシンアダプターShcの脳における機能的役割 (2018)
  • Author(s): 柿澤 昌
  • Journal Title: 日本薬理学雑誌 Volume: 印刷中
  • NAID: 130007432230
  • Peer Reviewed
• [Journal Article] 脳機能とその破綻に対する時間・階層縦断的アプローチと治療戦略 序文 (2017)
  • Author(s): 柿澤 昌, 森口 茂樹
  • Journal Title: 日本薬理学雑誌 Volume: 150 Pages: 217-217
• [Journal Article] Effects of reactive oxygen species on synaptic plasticity in CNS in relation to aging (2017)
  • Author(s): 柿澤 昌
  • Journal Title: Folia Pharmacologica Japonica Volume: 150 Issue: 5 Pages: 234-239
  • DOI: 10.1254/fpj.150.234
  • NAID: 130006198417
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Mice lacking the intracellular cation channel TRIC-B have compromised collagen production and impaired bone mineralization. (2016)
  • Author(s): C.Zhao, A.Ichimura, N.Qian, T.Iida, D.Yamazaki, N.Noma, M.Asagiri, K.Yamamoto, S.Komazaki, C.Sato, F.Aoyama, A.Sawaguchi, S.Kakizawa, M.Nishi, and H.Takeshima.
  • Journal Title: science signaling Volume: 9 Issue: 428
  • DOI: 10.1126/scisignal.aad9055
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Involvement of the neuronal phosphotyrosine signal adaptor N-Shc in kainic acid-induced epileptiform activity (2016)
  • Author(s): Baba S, Onga K, Kakizawa S, Ohyama K, Yasuda K, Otsubo H, Scott BW, Burnham WM, Matsuo T, Nagata I, Mori N
  • Journal Title: Scientific Reports Volume: 6 Issue: 1
  • DOI: 10.1038/srep27511
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nitric Oxide-induced Activation of the Type 1 Ryanodine Receptor Is Critical for Epileptic Seizure-induced Neuronal Cell Death (2016)
  • Author(s): Mikami, Y., Kanemaru, K., Okubo, Y., Nakaune, T., Suzuki, J., Shibata, K., Sugiyama, H., Koyama, R., Murayama, T., Ito, A., Yamazawa, T., Ikegaya, Y., Sakurai, T., Saito, N., Kakizawa, S. and Iino, M.
  • Journal Title: EBioMedicine. Volume: 11 Pages: 253
  • DOI: 10.1016/j.ebiom.2016.08.020
  • Peer Reviewed / Open Access
• [Journal Article] Essential Roles of Natural Products and Gaseous Mediators on Neuronal Cell Death or Survival (2016)
  • Author(s): Mikami Y, Kakizawa S, Yamazawa T
  • Journal Title: International Journal of Molecular Sciences Volume: 17 Issue: 10 Pages: 1652-1652
  • DOI: 10.3390/ijms17101652
  • NAID: 120005997697
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nitric-oxide induced calcium release: regulatory mechanism and physiological function (2016)
  • Author(s): 柿澤 昌、山澤徳志子
  • Journal Title: Folia Pharmacologica Japonica Volume: 147 Issue: 4 Pages: 194-199
  • DOI: 10.1254/fpj.147.194
  • NAID: 130005143841
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Nitric oxide-induced calcium release: neuronal cell death (2016)
  • Author(s): 山澤 徳志子、柿澤 昌
  • Journal Title: Folia Pharmacologica Japonica Volume: 147 Issue: 4 Pages: 200-205
  • DOI: 10.1254/fpj.147.200
  • NAID: 130005143839
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Mitsugumin 56 (hedgehog acyltransferase-like) is a sarcoplasmic reticulum-resident protein essential for postnatal muscle maturation. (2015)
  • Author(s): Van B, Nishi M, Komazaki S, Ichimura A, Kakizawa S, Nakanaga K, Aoki J, Park KH, Ma J, Ueyama T, Ogata T, Maruyama N, Takeshima H.
  • Journal Title: FEBS Lett. Volume: in press Issue: 10 Pages: 1095-1104
  • DOI: 10.1016/j.febslet.2015.03.028
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 小脳シナプスの加齢に伴う機能低下のシグナリング機構と抗老化へのアプローチ (2019)
  • Author(s): 柿澤 昌
  • Organizer: 第92回日本薬理学会年会シンポジウム
  • Invited
• [Presentation] レドックスシグナルによる小脳依存的運動学習の制御 (2018)
  • Author(s): 柿澤 昌
  • Organizer: 第71回日本酸化ストレス学会・第18回日本NO学会合同学術集会シンポジウム
  • Invited
• [Presentation] S-nitrosylation of the type 1 ryanodine receptor is critical for epileptic seizure-induced neuronal cell death (2017)
  • Author(s): 三上 義礼, 金丸 和典, 大久保 洋平, 中畝 拓哉, 鈴木 純二, 柿澤 昌, 柴田 和輝, 小山 隆太, 村山 尚, 伊藤 明博, 山澤 徳志子, 伊藤 雅方, 冨田 太一郎, 村上 慎吾, 赤羽 悟美, 池谷 裕二, 櫻井 隆, 齊藤 延人, 飯野 正光
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松 (静岡県・浜松市)
  • Year and Date: 2017-03-28
• [Presentation] 小脳プルキンエ細胞におけるカルシウムストアの維持・制御機構 (2017)
  • Author(s): 柿澤 昌
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール (長崎県・長崎市)
  • Year and Date: 2017-03-15
  • Invited
• [Presentation] 脳におけるレドックスシグナルの生理的役割とクロストーク (2017)
  • Author(s): 柿澤 昌
  • Organizer: 第94回日本生理学会年会
  • Place of Presentation: 長崎ブリックホール (長崎県・長崎市)
  • Year and Date: 2017-03-15
  • Invited
• [Presentation] Involvement of Nitric oxide-induced calcium release through type 1 ryanodine receptor in extinction of cerebellum-dependent motor learning (2017)
  • Author(s): Kakizawa S, Kishimoto Y, Miyazaki T, Mikami Y, Murayama T, Nagai M, Yamamoto S, Yamazaki D, Ichimura A, Yamazawa T, Adachi-Akahane S, Watanabe M, Iino M
  • Organizer: 20th International Symposium on Calcium Binding Proteins and Calcium Function in Health and Disease (CaBP20)
  • Int'l Joint Research
• [Presentation] 一酸化窒素は1型リアノジン受容体のS -ニトロシル化修飾を介して神経細胞死を誘導する (2016)
  • Author(s): 三上 義礼, 金丸 和典, 大久保 洋平, 中畝 拓哉, 鈴木 純二, 柿澤 昌, 村山 尚, 柴田 和輝, 小山 隆太, 伊藤 明博, 山澤 徳志子, 伊藤 雅方, 冨田 太一郎, 村上 慎吾, 赤羽 悟美, 櫻井 隆, 池谷 裕二, 齊藤 延人, 飯野 正光
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川県・横浜市)
  • Year and Date: 2016-11-30
• [Presentation] Involvement of Cerebellar LTP induced by Nitric Oxide-Induced Ca2+ Release in Extinction of Eyeblink Conditioning (2016)
  • Author(s): Kakizawa S, Kishimoto Y, Miyazaki T, Murayama T, Tanaka M, Yamamoto S, Yamazaki D, Nishi M, Yamazawa T, Watanabe M, Takeshima H, Iino M
  • Organizer: The 10th Forum of European Neuroscience
  • Place of Presentation: コペンハーゲン (デンマーク)
  • Year and Date: 2016-07-02
  • Int'l Joint Research
• [Presentation] Nitric oxide-induced calcium release: S-nitrosylation of the type 1 ryanodine receptor and neuronal cell death (2016)
  • Author(s): 三上 義礼, 金丸 和典, 小田 康弘, 柿澤 昌, 柴田 和輝, 杉山 弘樹, 小山 隆太, 伊藤 明博, 村山 尚, 山澤 徳志子, 渡辺 雅彦, 池谷 裕二, 斉藤 延人, 桜井 隆, 飯野 正光
  • 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(北海道・札幌市)
  • Year and Date: 2016-03-22
• [Presentation] 小脳依存的運動学習の書き換えと加齢の影響 (2016)
  • Author(s): 柿澤 昌
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県・横浜市)
  • Year and Date: 2016-03-09
• [Presentation] 1型リアノジン受容体のS-ニトロシル化が引き起こす神経細胞死 (2016)
  • Author(s): 三上 義礼, 金丸 和典, 小田 康弘, 柿澤 昌, 柴田 和輝, 杉山 弘樹, 小山 隆太, 伊藤 明博, 村山 尚, 山澤 徳志子, 渡辺 雅彦, 池谷 裕二, 斉藤 延人, 桜井 隆, 飯野 正光
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県・横浜市)
  • Year and Date: 2016-03-09
• [Presentation] 1型リアノジン受容体のS-ニトロシル化を介した神経細胞死の誘導 (2015)
  • Author(s): 三上 義礼, 金丸 和典, 小田 康弘, 伊藤 明博, 柿澤 昌, 山澤 徳志子, 斉藤 延人, 飯野 正光
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場(兵庫県・神戸市)
  • Year and Date: 2015-07-28
• [Presentation] 新規カルシウム放出機構「一酸化窒素依存的カルシウム放出」と小脳依存性運動学習への関与 (2015)
  • Author(s): 柿澤 昌, 岸本 泰司, 宮崎 太輔, 田中 碧, 村山 尚, 渡辺 雅彦, 飯野 正光, 竹島 浩
  • Organizer: 第15回日本NO学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪府・豊中市)
  • Year and Date: 2015-06-26
• [Book] 脳内環境辞典 (2017)
  • Author(s): 柿澤 昌
  • Total Pages: 158
  • Publisher: メディカル・ドゥ
  • ISBN: 9784944157648
• [Book] レドックスシグナル in 脳内環境辞典 (2017)
  • Author(s): 柿澤 昌
  • Total Pages: 156
  • Publisher: メディカルドゥ
• [Book] Nitric Oxide. In Essentials of cerebellum and cerebellar disorders (2016)
  • Author(s): Kakizawa S
  • Total Pages: 656
  • Publisher: Springer
• [Book] Nitric Oxide (in Essentials of Cerebellum and Cerebellar Disorders) (2016)
  • Author(s): Kakizawa, S.
  • Publisher: Springer
• [Book] Somatolactin (in "Handbook of Hormones") (2015)
  • Author(s): Kakizawa, S.
  • Total Pages: 646
  • Publisher: Elsevier (Tokyo)
• [Book] Apelin (in "Handbook of Hormones") (2015)
  • Author(s): Kakizawa, S.
  • Total Pages: 646
  • Publisher: Elsevier (Tokyo)
• [Book] Critical Roles of Oxidative Signals in Age-Related Decline of Cerebellar Synaptic Plasticity (in "Aging Mechanisms: Longevity, Metabolism, and Brain Aging") (2015)
  • Author(s): Kakizawa, S., Mori, N.
  • Total Pages: 439
  • Publisher: Springer (Tokyo)