G-protein independent signaling induced by be-ta blocker and the significance of the signaling.

• Project/Area Number: 20790066
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Kyushu University
• Principal Investigator: NAKAYA Michio Kyushu University, 薬学研究院, 助教 (80464387)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2008: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 薬理学 / シグナル伝達 / G蛋白質 / BRET / FRET

Research Abstract

Metoprolol is one of antagonists specific for the β1 adrenergic receptor. We accidentally found that long-term administration of metoprolol induced cardiac fibrosis in mice. This fibrosis signal by metoprolol is mediated by β1 adrenergic receptor in a G protein-independent fashion and requires ERK activation. We also demonstrate that the signal pathway depends on β-arrestin2 and GRK5. Indeed, the cardiac fibrosis was not observed when the metoprolol was administered to β-arrestin2 or GRK5 deficient mice.

Research Products

• [Journal Article] Determining the activation of Rho as an index of coupling to G12/13. Chapter for "Receptor Signal Transduction Protocols" (2010)
  • Author(s): Nakaya M, Ohba M, Nishdia M, Kurose H
  • Journal Title: "Methods in Molecular Biology" series(Humana Press) Vol.83
• [Journal Article] Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition. (2010)
  • Author(s): Nishida M, Watanabe K, Sato Y, Nakaya M, Kitajima K, Ide T, Inoue R, Kurose H
  • Journal Title: J. Biol. Chem. 285 Pages: 13244-13253
  • Peer Reviewed
• [Journal Article] 三量体g蛋白質シグナリングを介した心不全発症の分子機構 (2010)
  • Author(s): 西田基宏, 大場三奈, 仲矢道雄, 黒瀬, 等
  • Journal Title: 日本薬理学雑誌 (in press)
• [Journal Article] βアドレナリン受容体 (2010)
  • Author(s): 仲矢道雄, 大場三奈, 黒瀬, 等
  • Journal Title: 医学のあゆみ Vol.233,No.9
• [Journal Article] ジアシルグリセロール感受性TRPCチャネルを介した心肥大誘導のメカニズム (2010)
  • Author(s): 西田基宏, 渡辺健太, 仲矢道雄, 黒瀬, 等
  • Journal Title: YAKUGAKU ZASSHI Vol.130,No.3 Pages: 295-302
  • NAID: 130000259511
• [Journal Article] Phosphorylation of TRPC6 channels at Thr69 is required foranti-hypertrophic effects of phosphodiesterase 5 inhibition. (2010)
  • Author(s): Nishida M, et al.
  • Journal Title: J.Biol.Chem. (in press)
  • Peer Reviewed
• [Journal Article] Pertussis toxin upregulates angiotensin type 1 receptors through Toll-like receptor 4-mediated Rac activation. (2010)
  • Author(s): Nishida M, et al.
  • Journal Title: J.Biol.Chem. (in press)
  • Peer Reviewed
• [Journal Article] 貪食過程における低分子量G蛋白質Rac1とRab5の活性変化 (2009)
  • Author(s): 中村岳史, 北野正寛, 仲矢道雄, 長田重一, 松田道行
  • Journal Title: PNE 6月増刊号 Pages: 1114-1118
• [Journal Article] G12/13タンパク質による活性酸素シグナリング (2009)
  • Author(s): 西田基宏, 仲矢道雄, 黒瀬, 等
  • Journal Title: 実験医学増刊 Vol.27,No.15
• [Journal Article] Gタンパク質共役型受容体-TRPCチャネルタンパク複合体形成による心肥大シグナル制御 (2009)
  • Author(s): 西田基宏, 佐藤陽治, 仲矢道雄, 黒瀬, 等
  • Journal Title: 日本薬理学雑誌 Vol.134,No.3 Pages: 131-136
  • NAID: 10025741479
• [Journal Article] Spatiotemporal activation of Rac1 for engulfment of apoptotic cells. (2008)
  • Author(s): Nakaya M, Kitano M, Matsuda M, Nagata S
  • Journal Title: Pro Natl Acad Sci USA 105 Pages: 9198-9203
  • Peer Reviewed
• [Journal Article] Imaging of Rab5 activity identifies essential regulators for phagosome maturation. (2008)
  • Author(s): Kitano M, Nakaya M, Nakamura T, Nagata S, Matsuda M
  • Journal Title: Nature 453 Pages: 241-245
  • Peer Reviewed
• [Journal Article] P2Y_6 Receptor-Gα_<12/13> Signaling in Cardiomyocytes Triggers Pressure Overload-induced Cardiac Fibrosis. (2008)
  • Author(s): Nishida M, Sato Y, Uemura A, Narita Y, Tozaki-Saitoh H, Nakaya M, Ide T, Suzuki K, Inoue K, Nagao T, Kurose H
  • Journal Title: EMBO J. 27 Pages: 3104-3115
  • Peer Reviewed
• [Journal Article] 機械的伸展刺激により活性化されるGタンパク質共役型受容体の解析 (2008)
  • Author(s): 西田基宏, 上村綾, 仲矢道雄, 黒瀬, 等
  • Journal Title: 表面(広信社) Vol.46,No.3
• [Journal Article] Rab5活性のイメージングにより同定されたファゴソーム成熟に必須の制御因子 (2008)
  • Author(s): 北野正寛, 仲矢道雄, 中村岳史, 長田重一, 松田道行
  • Journal Title: 細胞工学 9月号 Pages: 904-905
• [Journal Article] Spatiotemporal activation of Racl for engulfment of apoptotic cells (2008)
  • Author(s): Nakaya M, et.al.
  • Journal Title: Proc. Natl. Acad. Sci. USA 105 Pages: 9198-9203
  • Peer Reviewed
• [Journal Article] Imaging of Rab5 activity identifies essential regulators for phagosome maturation (2008)
  • Author(s): Kitano M, et.al.
  • Journal Title: Nature 453
  • Peer Reviewed
• [Journal Article] P2Y6 receptor-Galphal2/13 signalling in cardiomyocytes triggers press ure overload-induced cardiac fibrosis (2008)
  • Author(s): Nishida M, et.al.
  • Journal Title: EMBO. J 27 Pages: 3104-3115
  • Peer Reviewed
• [Journal Article] Heterotrimeric G proteins in heart failure. Heart Failure: Symptoms, Causes and Treatment Options.
  • Author(s): Nishida M, Ohba M, Nakaya M, Kurose H
  • Journal Title: Nova Science Publishers (in press)
• [Journal Article] Pertussis toxin upregulates angiotensin type1 receptors through TLR4-mediated Rac activation.
  • Author(s): Nishida M, Suda R, Tanabe S, Onohara N, Nakaya M, Kanaho Y, Sumimoto H, Sato Y, Kurose H
  • Journal Title: J. Biol. Chem. (in press)
  • Peer Reviewed
• [Presentation] β遮断薬の新しい薬理作用 (2010)
  • Author(s): 仲矢道雄
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: (岡山)シンポジウム
  • Year and Date: 2010-03-28
• [Presentation] β遮断薬の新しい薬理作用 (2010)
  • Author(s): 仲矢道雄
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-28
• [Presentation] Spatiotemporal activation of Rac1 for engulfment of apoptotic cells. (2009)
  • Author(s): Nakaya M, Kitano M, Matsuda M, Nagata S
  • Organizer: IUPS2009 (第36回国際生理学会世界大会)
  • Place of Presentation: Kyoto
  • Year and Date: 2009-07-29
• [Presentation] アポトーシス細胞の貪食におけるRac1の空間的・時間的活性化 (2008)
  • Author(s): 仲矢道雄、北野正寛、松田道行、長田重一
  • Organizer: 生化学会・分子生物学会合同大会BMB2008
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] アポトーシス細胞の貧食におけるRac1の空間的・時間的活性化 (2008)
  • Author(s): 仲矢道雄
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Book] YAKUGAKU ZASSHI Review 130巻3号 (2010)
  • Author(s): 西田基宏, ら計4名
  • Publisher: 日本薬学会
• [Book] 日本薬理学会雑誌「Gタンパク質共役型受容体」134巻3号 (2009)
  • Author(s): 西田基宏, ら計4名
  • Publisher: 日本薬理学会
• [Book] 実験医学 増刊号 「活性酸素シグナルと酸化ストレス」 (2009)
  • Author(s): 西田基宏, ら計3名
  • Publisher: 羊土社
• [Book] 蛋白質核酸酵素 6月増刊号 「感染現象」 (2009)
  • Author(s): 中村岳史, ら計5名
  • Publisher: 共立出版
• [Remarks]
  • URL: http://chudoku.phar.kyushu-u.ac.jp/index.html
• [Remarks]
  • URL: http://210.233.60.66/~chudoku/