Regulation of extracellular matrix homeostasis via amino acid-operated cation channels

• Project/Area Number: 23659042
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Kyushu University
• Principal Investigator: NISHIDA Motohiro 九州大学, 薬学研究院, 准教授 (90342641)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: シグナル伝達 / イオンチャネル / アミノ酸 / 細胞外マトリクス / カルシウム / 薬学 / 心血管 / 細胞外マトリックス

Research Abstract

Amino acids in vivo work not only as components of proteins, but also specificligands activating intracellular nutrition signalings. Although collapse of amino acid balance in vivo has been implicated in the development of several diseases, molecular target(s) connecting amino acid imbalance directly to diseases have not been identified. We identified proline-activated cation channel (PRAC), which is directly activated by extracellular matrix-composing amino acids, such as proline, hydroxyproline, alanine, and glycine. We demonstrated that diacylglycerol-activated transient receptor potential canonical (TRPC) channels (TRPC3 and TRPC6) participated as major components of PRAC in primary-cultured cardiomyocytes and cardiac fibroblasts. Deletion of TRPC3 or TRPC6 abolished amino acid-induced cation influx and subsequent increase in intracellular Ca2+concentration. We also found that autophagy was significantly induced in TRPC3- and TRPC6-deficient mouse hearts, and in cardiomyocytes treated with TRPC3/6 inhibitor. These findings strongly suggest that PRAC plays a critical role in protein recycling in the heart. On the other hand, overexpression of TRPC3 and TRPC6 conferred susceptibility to amino acid -induced Ca2+signaling in PRAC-nonexpressing cells. These results strongly suggest that TRPC3/6 heteromultimer channels function as PRAC.

Research Products

• [Journal Article] GRK6-deficient mice exhibit reduced recycling of senescent red blood cells and impaired apoptotic cell clearance causing autoimmunity (2013)
  • Author(s): Nakaya M, Tajima M, Kosako H, Nakaya T, Hashimoto A, Watari K, Nishihara H, Ohba M, Komiya S, Tani N, Nishida M, Taniguchi H, Sato Y, Matsumoto M, Tsuda M, Kuroda M, Inoue K, Kurose H
  • Journal Title: Nature Communications. Volume: 4 Pages: 1-11
  • DOI: 10.1038/ncomms2540
  • Peer Reviewed
• [Journal Article] Voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by angiotensin II in mice. (2013)
  • Author(s): Nishida M, Ishikawa T, Saiki S, Sunggip C, Aritomi S, Harada E, Kuwahara K, Hirano K, Mori Y, Kim-Mitsuyama S.
  • Journal Title: Biochem Biophys Res Commun. Volume: in press
  • Peer Reviewed
• [Journal Article] Regulation of redox signaling by an electrophilic cyclic nucleotide. (2013)
  • Author(s): Akaike T, Nishida M, Fujii S.
  • Journal Title: J. Biochem. Volume: 153(2) Pages: 131-138
  • NAID: 40019566342
  • Peer Reviewed
• [Journal Article] Redox control of cardiovascular homeostasis by Angiotensin II. (2013)
  • Author(s): Sunggip C, Kitajima N & Nishida M
  • Journal Title: Current Pharmaceutical Design. Volume: in press
  • Peer Reviewed
• [Journal Article] Induction of cardiac fibrosis by β-blocker in G protein-independent and GRK5/ β -arrestin2-dependent signaling pathways (2012)
  • Author(s): Nakaya M, Chikura S, Watari K, Mizuno N, Mochinaga K, Mangmool S, Koyanagi S, Ohdo S, Sato Y, Ide T, Nishida M, Kurose H
  • Journal Title: J. Biol. Chem Volume: 287(42) Pages: 35669-35677
  • Peer Reviewed
• [Journal Article] Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis (2012)
  • Author(s): Kan-o M, Takeya R, Abe T, Kitajima N, Nishida M, Tominaga R, Kurose H and Sumimoto H
  • Journal Title: Biol. Open Volume: 1(9) Pages: 889-896
  • Peer Reviewed
• [Journal Article] Recombinant mitochondrial transcription factor A protein inhibits nuclear factor of activated T cells signaling and attenuates pathological hypertrophy of cardiac myocytes (2012)
  • Author(s): Fujino T, Ide T, Yoshida M, Onitsuka K, Tanaka A, Hata Y, Nishida M, Takehara T, Kanemaru T, Kitajima N, Takazaki S, Kurose H, Kang D and Sunagawa K
  • Journal Title: Mitochondrion Volume: 12 Pages: 449-458
  • Peer Reviewed
• [Journal Article] Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration (2012)
  • Author(s): Nishida M, Sawa T, Kitajima N, Ono K, Inoue H, Ihara H, Motohashi H, Yamamoto M, Suematsu M, Kurose H, van der Vliet A, Freeman BA, Shibata T, Uchida K, Kumagai Y and Akaike T
  • Journal Title: Nature Chem. Biol Volume: 8 Pages: 714-724
  • Peer Reviewed
• [Journal Article] Induction of cardiac fibrosis by β-blocker in G protein-independent and GRK5/β-arrestin2-dependent signaling pathways. (2012)
  • Author(s): Nakaya M, Chikura S, Watari K, Mizuno N, Mochinaga K, Mangmool S, Koyanagi S, Ohdo S, Sato Y, Ide T, Nishida M, Kurose H.
  • Journal Title: J. Biol. Chem. Volume: 287(42) Pages: 35669-35677
  • Peer Reviewed
• [Journal Article] Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis. (2012)
  • Author(s): Kan-o M, Takeya R, Abe T, Kitajima N, Nishida M, Tominaga R, Kurose H and Sumimoto H.
  • Journal Title: Biol. Open. Volume: 1(9) Pages: 889-896
  • Peer Reviewed
• [Journal Article] Recombinant mitochondrial transcription factor A protein inhibits nuclear factor of activated T cells signaling and attenuates pathological hypertrophy of cardiac myocytes. (2012)
  • Author(s): Fujino T, Ide T, Yoshida M, Onitsuka K, Tanaka A, Hata Y, Nishida M, Takehara T, Kanemaru T, Kitajima N, Takazaki S, Kurose H, Kang D and Sunagawa K.
  • Journal Title: Mitochondrion. Volume: 12 Pages: 449-458
  • Peer Reviewed
• [Journal Article] Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration. (2012)
  • Author(s): Nishida M, Sawa T, Kitajima N, Ono K, Inoue H, Ihara H, Motohashi H, Yamamoto M, Suematsu M, Kurose H, van der Vliet A, Freeman BA, Shibata T, Uchida K, Kumagai Y and Akaike T.
  • Journal Title: Nat. Chem. Biol. Volume: 8 Pages: 714-724
  • Peer Reviewed
• [Journal Article] Protein kinase A-mediated phosphorylation of TRPC6 channels underlies suppression of angiotensin II-induced vasoconstriction. Arterioscler (2011)
  • Author(s): Nishioka K, Nishida M, Ariyoshi M, Saiki S, Jian Z, Hirano M, Nakaya M, Sato Y, Kita S, Iwamoto T, Hirano K, Inoue R and Kurose H
  • Journal Title: Thromb. Vasc. Biol Volume: 31 Pages: 2278-2286
  • Peer Reviewed
• [Journal Article] TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts (2011)
  • Author(s): Kitajima N, Watanabe K, Morimoto S, Sato Y, Kiyonaka S, Hoshijima M, Ikeda Y, Nakaya M, Ide T, Mori Y, Kurose H and Nishida M
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 409 Pages: 108-113
  • Peer Reviewed
• [Journal Article] Heterologous down-regulation of angiotensin type1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-・B (2011)
  • Author(s): Nishida M, Ogushi M, Suda R, Toyotaka M, Saiki S, Kitajima N, Nakaya M, Kim K-M, Ide T, Sato Y, Inoue K and Kurose H
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 108 Pages: 6662-6627
  • Peer Reviewed
• [Journal Article] Mechanism of the cardioprotective effects of docetaxel pre-administration against adriamycin-induced cardiotoxicity (2011)
  • Author(s): Tomonari M, To H, Nishida M, Mishima T, Sasaki H, and Kurose H
  • Journal Title: J. Pharmacol. Sci Volume: 115 Pages: 336-345
  • NAID: 10029892637
  • Peer Reviewed
• [Journal Article] Dual signaling pathways of arterial constriction by extracellular urine 5'-triphosphate in the rat (2011)
  • Author(s): Sugihara M, Morita H, Matsuda M, Umebayashi H, Kajioka S, Ito S, Nishida M, Inoue R, Futatsuki T, Yamazaki J, Mori Y, Inoue R, Ito Y, Abe K and Hirata M
  • Journal Title: J. Pharmacol. Sci Volume: 115 Pages: 293-308
  • Peer Reviewed
• [Journal Article] Protein kinase A-mediated phosphorylation of TRPC6 channels underlies suppression of angiotensin II-induced vasoconstriction. (2011)
  • Author(s): Nishioka K, Nishida M, Ariyoshi M, Saiki S, Jian Z, Hirano M, Nakaya M, Sato Y, Kita S, Iwamoto T, Hirano K, Inoue R, Kurose H
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. Volume: 31 Pages: 2278-2286
  • DOI: 10.1161/atvbaha.110.221010
  • Peer Reviewed
• [Journal Article] TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts. (2011)
  • Author(s): Kitajima N, Watanabe K, Morimoto S, Sato Y, Kiyonaka S, Hoshijima M, Ikeda Y, Nakaya M, Ide T, Mori Y, Kurose H, Nishida M
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 409 Pages: 108-113
  • DOI: 10.1016/j.bbrc.2011.04.124
  • Peer Reviewed
• [Journal Article] Heterologous down-regulation of angiotensin type1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-ｋB. (2011)
  • Author(s): Nishida M, Ogushi M, Suda R, Toyotaka M, Saiki S, Kitajima N, Nakaya M, Kim K-M, Ide T, Sato Y, Inoue K, Kurose H
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 108 Pages: 6662-6627
  • DOI: 10.1073/pnas.1017640108
  • Peer Reviewed
• [Journal Article] Dual Signaling Pathways of Arterial Constriction by Extracellular Uridine 5'-Triphosphate in the Rat (2011)
  • Author(s): Sugihara M, Morita H, Matsuda M, Umebayashi H, Kajioka S, Ito S, Nishida M, Inoue R, Futatsuki T, Yamazaki J, Mori Y, Inoue R, Ito Y, Abe K, Hirata M
  • Journal Title: J Pharmacol Sci Volume: 115 Issue: 3 Pages: 293-305
  • DOI: 10.1254/jphs.10281FP
  • NAID: 10029892471
  • Peer Reviewed
• [Journal Article] Voltage-dependent N-type Ca2+channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by angiotensin II in mice
  • Author(s): Nishida M, Ishikawa T, Saiki S, Sunggip C, Aritomi S, Harada E, Kuwahara K, Hirano K, Mori Y, Kim-Mitsuyama S
  • Journal Title: Biochem Biophys Res Commun Volume: (in press)
  • Peer Reviewed
• [Presentation] Regulation of cardiac homeostasis by hydrogen sulfide anion (2013)
  • Author(s): Nishida M
  • Organizer: The 90th annual meeting of the Physiological Society of Japan
  • Place of Presentation: Tokyo
• [Presentation] 硫化水素による心不全抑制の分子機構と創薬への応用 (2013)
  • Author(s): 西田基宏
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] Hydrogen sulfide suppresses H-Ras-mediated cardiac senescence after myocardial infarction via electrophile sulfhydration (2012)
  • Author(s): 西田基宏
  • Organizer: 第33回内藤コンファレンス Oxygen Biology, Hypoxia, Oxidative Stress and Diseases
  • Place of Presentation: Sapporo
• [Presentation] Sulfhydration of electrophiles underlies protection against reactive oxygen species-mediated cardiac senescence by hydrogen sulfide (2012)
  • Author(s): Nishida M
  • Organizer: The 33rd Naito Conference Oxygen Biology, Hypoxia, Oxidative Stress and Diseases
  • Place of Presentation: Sapporo
• [Presentation] 脂質活性化TRPCチャネルによる心血管リモデリング制御 (2012)
  • Author(s): 西田基宏
  • Organizer: 生体機能と創薬シンポジウム
  • Place of Presentation: 神戸
• [Presentation] ガス由来活性分子によるG蛋白質H-Rasのレドックス恒常性と心筋老化制御 (2012)
  • Author(s): 西田基博
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
• [Presentation] 心臓の線維化におけるジアシルグリセロール活性化型TRPCチャネルの役割 (2012)
  • Author(s): 西田基宏，北島直幸，仲矢道雄，黒瀬等
  • Organizer: 日本薬理学会年会
  • Place of Presentation: 京都
• [Presentation] 心臓リモデリングにおけるTRPCチャネルの役割 (2012)
  • Author(s): 西田基宏
  • Organizer: 細胞電気薬理研究会(招待講演)
  • Place of Presentation: 京都
• [Presentation] マウスにおいてL/N型Ca2+チャネルの持続的阻害は心不全を抑制する (2012)
  • Author(s): 北島直幸，斎木翔太，有冨静，石川達也，仲矢道雄，森泰生，黒瀬等，西田基宏
  • Organizer: 日本薬理学会年会
  • Place of Presentation: 京都
• [Presentation] 末梢循環障害におけるTRPC6チャネルの役割 (2012)
  • Author(s): 斎木翔太，角田将朗，佐藤陽治，仲矢道雄，岩本隆宏，黒瀬等，西田基宏
  • Organizer: 日本薬理学会年会
  • Place of Presentation: 京都
• [Presentation] 脂質活性化型TRPCチャネルによる心臓リモデリング制御 (2012)
  • Author(s): 西田基宏
  • Organizer: 第41回日本心脈管作動物質学会(招待講演)
  • Place of Presentation: 秋田
• [Presentation] Sulfhydration of Electrophiles Underlies Protection against Reactive Oxygen Species-mediated Cardiac Senescence by Hydrogen Sulfide (2011)
  • Author(s): 西田基宏
  • Organizer: New Aspects of Phospholipid Biology and Medicine 2011 (第10回 JBS バイオフロンティア国際シンポジウム)
  • Place of Presentation: Fukuoka
• [Book] Redox regulation of angiotensin receptor signaling in the heart. Angiotensin: New Research (2012)
  • Author(s): Nishida M*, Sunggip C, Kitajima N & Kurose H
  • Publisher: NOVA Publishers (New York)
• [Book] Angiotensin: New Research, Redox regulation of angiotensin receptor signaling in the heart. (2012)
  • Author(s): Nishida M, Sunggip C, Kitajima N & Kurose H
  • Total Pages: 15
  • Publisher: NOVA Publishers (New York), Edited by Harada S and Moi I.
• [Book] Angiotensin: New Research, Redox regulation of angiotensin receptor signaling in the heart. (2012)
  • Author(s): Nishida M, Sunggip C, Kitajima N & Kurose H
  • Total Pages: 10
  • Publisher: NOVA Publishers (New York)
• [Remarks] 研究室ホームページ
  • URL: http://soyaku.phar.kyushu-u.ac.jp/
• [Remarks] 高血圧治療薬アテレック（シルニジピン）に血管内皮保護効果
  • URL: http://www.phar.kyushu-u.ac.jp/bbs/view2.php?S_Publ_Year=2012&word=&page=1&B_Code=120
• [Remarks] シルニジピンはN型Caチャネル阻害を介しアンジオテンシンII誘発性の血管内皮障害を抑制
  • URL: http://medical.nikkeibp.co.jp/leaf/all/gakkai/jsh2012/201209/526847.html
• [Remarks] 硫化水素が心臓の老化を防ぐ仕組みを解明 〜心不全治療薬の開発に期待〜
  • URL: http://www.phar.kyushu-u.ac.jp/bbs/view2.php?S_Publ_Year=2012&word=&page=1&B_Code=113
• [Remarks] 硫化水素に心不全予防効果、細胞の老化抑える
  • URL: http://www.yomidr.yomiuri.co.jp/page.jsp?id=62058