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

2012 Fiscal Year Final Research Report

• 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
• Keywords: シグナル伝達 / イオンチャネル / アミノ酸

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 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance (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 Commun Volume: 4 Pages: 1532
  • DOI: DOI:10.1038/ncomms2540
  • 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] 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
  • 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] 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)
  • DOI: DOI:pii:S0006-291X(13)00456-7
  • Peer Reviewed
• [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
  • Year and Date: 20120626-29
• [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
  • Year and Date: 20111114-16
• [Book] Redox regulation of angiotensin receptor signaling in the heart. Angiotensin: New Research (2012)
  • Author(s): Nishida M*, Sunggip C, Kitajima N & Kurose H
  • Total Pages: 165-179
  • Publisher: NOVA Publishers (New York)
• [Remarks] 研究室ホームページ
  • URL: http://soyaku.phar.kyushu-u.ac.jp/