Analysis of behavioral quantity by the loss of function of CIN85 related to receptor endocytosis

• Project/Area Number: 18590216
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental physiology (including Physical medicine and Nutritional physiology)
• Research Institution: Gunma University
• Principal Investigator: SHIMOKAWA Noriaki Gunma University, 大学院・医学系研究科, 准教授 (90235680)
• Co-Investigator(Kenkyū-buntansha): KOIBUCHI Noriyuki 群馬大学, 大学院・医学系研究科, 教授 (80234681)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,880,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥480,000); Fiscal Year 2008: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: CIN85 / ドーパミン受容体 / 多動性 / エンドサイトーシス / ノックアウトマウス / 恐怖記憶 / 海馬 / 行動量 / ドーパミン系 / シナプス / 記憶 / 行動解析 / CIN85ノックアウトマウス / 多動 / ドーパミン システム / 受容体エンドサイトーシス / Scaffold protein / 記憶・学習

Research Abstract

CIN85ノックアウト(KO)マウスの「多動」の原因としてドーパミン及びその受容体の量的、質的変化に焦点をあてて解析した。電気化学検出器(本科研費にて購入)を備えた高速液体クロマトグラフィーでKOマウスの線条体ドーパミン含量を測定した結果、KOマウスでは野生型に比べて線条体ドーパミン含量が170%高値であった。さらに線条体初代培養細胞においてドーパミン刺激後、膜表面に存在するドーパミン受容体は野生型由来で約25%、KOマウスでは70%であった。このエンドサイトーシスの異常がドーパミン刺激の過剰を招き「多動」を誘発している原因の一つと考えられる。本研究から「多動」という行動異常の原因の一つが受容体の膜輸送を司る複合体の分子欠損によることが明らかになった。これは受容体によるシグナルの調節が受容体単一ではなく、多様な膜蛋白質の複合体形成によってもたらされている事を示している点で意義ある成果と考えられる。

Research Products

• [Journal Article] Increase in Cerebellar Neurotrophin-3 and Oxidative Stress Markers in Autism (2009)
  • Author(s): Sajdel-Sulkowska EM, Xu M, Koibuchi N
  • Journal Title: Cerebellum (in press)
  • Peer Reviewed
• [Journal Article] Augmentation of estrogen receptor-mediated transcription by steroid and xenobiotic receptor (2008)
  • Author(s): Rokutanda N, Iwasaki T, Odawara H, Nagaoka R, Miyazaki W, Takeshita A, Koibuchi Y, Horiguchi J, Shimokawa N, Iino Y, Morishita Y, Koibuchi N
  • Journal Title: Endocrine (in press)
  • Peer Reviewed
• [Journal Article] Identification of the functional domain of thyroid hormone receptor responsible for polychlorinated biphenyl-mediated suppression of its action in vitro (2008)
  • Author(s): Miyazaki W, Iwasaki T, Takeshita ATohyama C, Koibuchi N
  • Journal Title: Environ Health Perspect 116 Pages: 1231-1236
  • Peer Reviewed
• [Journal Article] Abnormalities of vertebral formation and Hox expression in congenital kyphoscoliotic rat (2008)
  • Author(s): Seki T, Shimokawa N, Iizuka H, Takagishi K, Koibuchi N
  • Journal Title: Mol. Cell. Bioche 312 Pages: 193-199
  • Peer Reviewed
• [Journal Article] The role of thyroid hormone in developing cerebellum (2008)
  • Author(s): Koibuchi N, Qiu CH, Miyazaki W, Iwasaki T, Shimokawa N
  • Journal Title: Cerebellum 7 Pages: 499-500
  • NAID: 130005448782
  • Peer Reviewed
• [Journal Article] Ahmadiani A. Low-dose morphine induces hyperalgesia through activation of Gas, protein kinase C and L-type Ca^2+ channels in rats (2008)
  • Author(s): Mahani SE, Shimokawa N, Javan M, Maghsodi N, Motamedi F, Koibuchi N
  • Journal Title: J. Neurosci. Res 86 Pages: 471-479
  • Peer Reviewed
• [Journal Article] The role of thyroid hormone in developing cerebellum. (2008)
  • Author(s): Koibuchi N, Qiu CH, Miyazaki W, Iwasaki T, Shimokawa N.
  • Journal Title: Cerebellum 7 Pages: 499-500
  • NAID: 130005448782
  • Peer Reviewed
• [Journal Article] Augmentation of estrogen receptor-mediated transcription by steroid and xenobiotic receptor. (2008)
  • Author(s): Rokutanda N, Iwasaki T, Odawara H, Nagaoka R, Miyazaki W, Takeshita A, Koibuchi Y, Horiguchi J, S himokawa N, Iino Y, Morishita Y, Koibuchi N.
  • Journal Title: Endocrine (In press)
  • Peer Reviewed
• [Journal Article] Abnormalities of vertebral formation and Hox expression in congenital kyphoscoliotic rats. (2008)
  • Author(s): Seki T, Shimokawa N, Iizuka H, Takagishi K, Koibuchi N.
  • Journal Title: Molecular and Cellular Biochemistry 312 Pages: 193-199
  • Peer Reviewed
• [Journal Article] Low-dose morphine induces hyperalgesia through activation of Gas, protein kinase C and L-type Ca^<2+> channels in rats. (2008)
  • Author(s): Mahani SE, Shimokawa N, Javan M, Maghsodi N, Motamedi F, Koibuchi N, Ahmadiani A.
  • Journal Title: Joumal of Neuroscience Research 86 Pages: 471-479
  • Peer Reviewed
• [Journal Article] Abnormalities of vertebral formation and Hox expression in congenital kyphoscoliotic rat (2008)
  • Author(s): Seki T, Shimokawa N, Iizuka H, Takagishi K, Koibuchi N.
  • Journal Title: Molecular and Cellular Biochemistry 312 Pages: 193-199
  • Peer Reviewed
• [Journal Article] RORa mutation in Staggerer mouse induces alteration of mRNA levels of neurotrophin family in developing cerebellum (2007)
  • Author(s): Qiu CH, Shimokawa N, Iwasaki T, Parhar IS, Koibuchi N
  • Journal Title: Endocrinology 148 Pages: 1745-1753
  • Peer Reviewed
• [Journal Article] 生殖生理学:性分化の仕組みとその異常 (2007)
  • Author(s): 下川 哲昭
  • Journal Title: 日本生理学会誌 69 Pages: 314-322
• [Journal Article] RORα mutation in Staggerer mouse induces alteration of mRNA levels of neurotrophin family in developing cerebellum. (2007)
  • Author(s): Qiu CH, Shimokawa N, Iwasaki T, Parhar IS, Koibuchi N.
  • Journal Title: Endocrinology 148 Pages: 1745-1753
• [Journal Article] Low dose hydroxylated PCB induces c-Jun expression in PC12 cells (2006)
  • Author(s): Shimokawa N, Miyazaki W, Iwasaki T, Koibuchi N
  • Journal Title: Neurotoxicology 27 Pages: 176-183
  • Peer Reviewed
• [Journal Article] The adrenal gland is a source of stress-induced circulating IL-18 (2006)
  • Author(s): Sugama S, Wang N, Shimokawa N, Koibuchi NFujita M, Hashimoto M, Dhabhar FS, Conti B
  • Journal Title: J. Neuroimmunol 172 Pages: 59-65
  • Peer Reviewed
• [Journal Article] Tamoxifen activates CYP3A4 and MDR-1 genes though steroid and xenobiotic receptor in breast cancer cells (2006)
  • Author(s): Nagaoka R, Iwasaki T, Rokutanda N, Takeshita A, Koibuchi Y, Horiguchi J, Shimokawa N, Iino Y, Morishita Y, Koibuchi N
  • Journal Title: Endocrine 30 Pages: 261-268
  • Peer Reviewed
• [Journal Article] Low dose hydroxylated PCB induces c-Jun expression in PC12 cells. (2006)
  • Author(s): Shimokawa N, Miyazaki W, Iwasaki T, Koibuchi N.
  • Journal Title: Neurotoxicology 27 Pages: 176-183
• [Journal Article] The adrenal gland is a source of stress-induced circulating IL-18. (2006)
  • Author(s): Sugama S, Wang N, Shimokawa N, Koibuchi N, Fujita M, Hashimoto M, Dhabhar FS, Conti B.
  • Journal Title: Journal of Neuroimmunology 172 Pages: 59-65
• [Journal Article] Tamoxifen activates CYP3A4 and MDR-1 genes though steroid and xenobiotic receptor in breast cancer cells. (2006)
  • Author(s): Nagaoka R, Iwasaki T, Rokutanda N, Takeshita A, Koibuchi Y, Horiguchi J, Shimokawa N, Iino Y, Morishita Y, Koibuchi N.
  • Journal Title: Endocrine 31(In press)
• [Journal Article] 甲状腺ホルモンによる脳発達の調節機構と環境化学物質による修飾 (2006)
  • Author(s): 鯉淵典之, 下川哲昭, 岩崎俊晴
  • Journal Title: 神経研究の進歩 50 Pages: 833-841
• [Presentation] トランスポートソームの機能破綻による神経性異常とヒトにおける病態解析 (2008)
  • Author(s): 下川哲昭
  • Organizer: 平成20年度特定領域研究班会議「生体膜トランスポートソームの分子機構と生理機能」
  • Place of Presentation: 兵庫
  • Year and Date: 2008-09-25
• [Presentation] CIN85機能欠失は神経伝達物質受容体のエンドサイトーシスを低下させ多動を引き起こす (2008)
  • Author(s): 下川哲昭
  • Organizer: 平成20年度隼理学研究所研究会「シナプス可塑性の分子的基盤」
  • Place of Presentation: 岡崎
  • Year and Date: 2008-06-05
• [Presentation] Analysis of nursing ability and lactational function of CIN85^<Δex2> deficient mice (2008)
  • Author(s): 池澤 淳, 青塚 伸孝, 伊藤 元治, 茶山 和敏, 下川 哲昭, 鯉淵 典之
  • Organizer: 第85回 日本生理学会大会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-26
• [Presentation] A novel mechanism of nuclear hormone receptor-mediated transcriptional regulation by TRBP-CoAA/CoAM-SRA cofactors (2008)
  • Author(s): 岩崎 俊晴, ロンドニョ マリーナ, 宮崎 航, 下川 哲昭, 鯉淵 典之
  • Organizer: 第85回 日本生理学会大会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-26
• [Presentation] The effect of retinoic acid receptor-related orphan nuclear receptor α on apo al and malic enzyme gene expression (2008)
  • Author(s): 加藤 雅世, 須田 真千子, 岩崎 俊晴, 邱 春紅, 天野 出月, ロンドニョ マリーナ, 宮崎 航, 下川 哲昭, 鯉淵 典之
  • Organizer: 第85回 日本生理学会大会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-26
• [Presentation] Phenotype analysis of CIN85^<Δex2> deficient mice (2008)
  • Author(s): 下川 哲昭, 邸 春紅, ロンドニョ マリーナ, 鯉淵 典之
  • Organizer: 第85回 日本生理学会大会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-25
• [Presentation] Degradation of TrkA is regulated through ubiquitination by Nedd4 and Cbl (2008)
  • Author(s): 森田 晶人, マハニ サイート, マハニ シーマ, ロンドニョ マリーナ, 下川 哲昭, 鯉淵 典之
  • Organizer: 第85回 日本生理学会大会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-25
• [Presentation] CIN85△ex2 knockout mice are hyperactive due to defective dopamine receptor endocvtosis in the brain. (2008)
  • Author(s): Shimokawa N., Haglund K., Kirkin V., Hoelter-Koch S.M., Dikic I.
  • Organizer: EMBO Meeting on Cellular Signaling & Molecular Medicine
  • Place of Presentation: Cavtat/Dubrovnik, Croatia
• [Presentation] Effect of polychlorinated biphenyl(PCB)on thyroid hormone receptor(TR)-retinoic acid receptor-related orphan receptor(ROR)crosstalk and its mechanism in develonine brain (2008)
  • Author(s): Iwasaki T., Qiu C.H., Amano I. Miyazaki W., Shimokawa N., Koibuchi N.
  • Organizer: 6th Forum of European Neuroscience
  • Place of Presentation: Geneva, Switzerland
• [Presentation] CIN85△ex2 knockout mice are hyperactive due to defective dopamine receptor endocytosis in the brain. (2008)
  • Author(s): Shimokawa N.
  • Organizer: III Curso de Biologfa Moleculary Simposio Patologias Endocrinas De Enfoque Multidisciplinario
  • Place of Presentation: Bogota, Colombia
• [Presentation] 受容体の膜輸送と分解を制御するCIN85の機能解析 (2007)
  • Author(s): 下川 哲昭, ロンドニョ マリーナ, 邱 春紅, 鯉淵 典之
  • Organizer: 第80回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-12
• [Presentation] 甲状腺ホルモン受容体及びRetinoic acid Receptor-related Orphan Receptor(ROR)を介する転写へのPCBの影響 (2007)
  • Author(s): 岩崎 俊晴, 邸 春紅, 天野 出月, 加藤 雅世, 須田 真千子, ロンドニョ マリーナ, 宮崎 航, 下川 哲昭, 鯉淵 典之
  • Organizer: 第10回環境ホルモン学会研究発表会
  • Place of Presentation: 大宮
  • Year and Date: 2007-12-10
• [Presentation] 受容体の膜輸送と分解を制御するCIN85の機能解析 (2007)
  • Author(s): 下川 哲昭
  • Organizer: 静岡大学 生命科学若手フォーラム
  • Place of Presentation: 静岡
  • Year and Date: 2007-09-20
• [Presentation] 発達期小脳における甲状腺ホルモン受容体とRORαの相互作用 (2007)
  • Author(s): 邱 春紅, 岩崎 俊晴, 下川 哲昭, 宮崎 航, 鯉淵 典之
  • Organizer: 第34回 日本神経内分泌学会学術集会
  • Place of Presentation: 前橋
  • Year and Date: 2007-08-04
• [Presentation] CIN85欠損マウスの多動性はドーパミン受容体のエンドサイトーシスの異常による (2007)
  • Author(s): 下川 哲昭
  • Organizer: 平成19年度 特定領域研究班会議 「生体膜トランスポートソームの分子機構と生理機能」
  • Place of Presentation: 神奈川
  • Year and Date: 2007-07-25
• [Presentation] げっ歯類小脳における周産期甲状腺機能低下症による発達異常とその分子機構 (2007)
  • Author(s): 鯉淵 典之, 邱 春紅, 下川 哲昭, 岩崎 俊晴
  • Organizer: 第80回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2007-06-15
• [Presentation] Low dose hydroxylated PCB disrupted Ca^<2+> homeostasis and plasma membrane potential. (2007)
  • Author(s): Londono M., Shimokawa N., Koibuchi N
  • Organizer: 27th International Symposium on Halogenated Pecrsistent Organic Pollutants
  • Place of Presentation: Tokyo
• [Presentation] Crosstalk between thyroid hormone receptor and retinoid receptor-related orphan receptor (ROR) aand its modulation bypolychlorinated biphenyl (2006)
  • Author(s): Koibuchi N., Qiu C.H., Miyazaki W., Shimokawa N., Iwasaki T.
  • Organizer: 36th Annual Meeting, Society for Neuroscience
  • Place of Presentation: Atlanta, GA, USA
• [Book] 生殖機能In : 集中講義「生理学」(岡田隆夫編) (2008)
  • Author(s): 下川哲昭
  • Publisher: メジカルビュー社
• [Book] 集中講義生理学 (2008)
  • Author(s): 岡田隆夫(編集)下川哲昭(分担)
  • Total Pages: 347
  • Publisher: Medical View社
• [Book] 内分泌生理症例問題他In症例問題から学ぶ生理学(鯉淵典之編)丸善 (2006)
  • Author(s): 鯉淵典之
  • Total Pages: 369
• [Book] Gene expression and signaling pathways by extracellular acidification. In : The Arterial Chemoreceptors (Hayashida, Gonzalez and Kondo, eds.) (2006)
  • Author(s): Shimokawa N, Londono M, Koibuchi N.
  • Total Pages: 362
  • Publisher: Springer