TRIC and MG23 channels in store Ca2+ handling

• Project/Area Number: 21H02663
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Kyoto University
• Principal Investigator: Takeshima Hiroshi 京都大学, 薬学研究科, 教授 (70212024)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: Ca2+ストア / 小胞体 / イオンチャネル / 成長板軟骨細胞 / Ca2+シグナル / マクロファージ / 骨格筋 / 小胞体Ca2+放出

Outline of Research at the Start

研究代表者が分子同定した小胞体膜タンパク質TRICおよびMG23はin vitro実験系で陽イオンチャネル活性を示すが、それぞれの生体内機能は十分に理解されていない。本研究においては、遺伝子欠損マウスとcDNA発現細胞のモデル実験系を駆使して、両チャネルの生理学的機能を究明し、疾患病態との連関も確立する。

Outline of Final Research Achievements

Tric-b-knockout mice provide an animal model of osteogenesis imperfecta. We found atypical cell death in Tric-b-knockout growth plate chondrocytes, that is caused by hyperactivation of the ER stress sensor PERK. In the muscle skinned fiber preparations from Mg23-knockout mice, we detected altered store Ca2+ handling, that is likely caused by insufficient Ca2+ leakage. Our observations indicate that TRIC and MG23 channels function as cation channels in sarco/endoplasmic reticulum and physiologically contribute to store Ca2+ handling.

Academic Significance and Societal Importance of the Research Achievements

小胞体Ca2+ストアは細胞機能に不可欠であり、様々な細胞応答を制御する。一方で、Ca2+ストアのイオンバランスの分子機序は未開拓な学術分野であり、その疾患病態との関連も不明である。当研究遂行による成果は、TRICおよびMG23チャネルのイオン透過性はCa2+ストア機能維持に不可欠であることを示し、TRIC-B欠損による骨形成不全症の発症メカニズムの解明に貢献した。

Research Products

• [Int'l Joint Research] Oxford University(英国)
• [Journal Article] Ca²⁺ storage function is altered in the sarcoplasmic reticulum of skeletal muscle lacking mitsugumin 23 (2024)
  • Author(s): Watanabe Daiki、Nishi Miyuki、Liu Feng、Bian Yuhan、Takeshima Hiroshi
  • Journal Title: American Journal of Physiology-Cell Physiology Volume: 326 Issue: 3 Pages: C795-C809
  • DOI: 10.1152/ajpcell.00440.2023
  • Peer Reviewed / Open Access
• [Journal Article] Soluble epoxide hydrolase maintains steady-state lipid turnover linked with autocrine signaling in peritoneal macrophages. (2023)
  • Author(s): Liu, F., Diao, X., Cong, H., Suzuki, E., Hasumi, K. & Takeshima, H.
  • Journal Title: iScience Volume: 26 Issue: 8 Pages: 107465-107465
  • DOI: 10.1016/j.isci.2023.107465
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac glycosides stimulate endocytosis of GLUT1 via intracellular Na+,K+‐ATPase α3‐isoform in human cancer cells (2022)
  • Author(s): Fujii Takuto、Katoh Mizuki、Ootsubo Manami、Nguyen Oanh T. T.、Iguchi Mayumi、Shimizu Takahiro、Tabuchi Yoshiaki、Shimizu Yasuharu、Takeshima Hiroshi、Sakai Hideki
  • Journal Title: Journal of Cellular Physiology Volume: 237 Issue: 7 Pages: 2980-2991
  • DOI: 10.1002/jcp.30762
  • Peer Reviewed / Open Access
• [Journal Article] C-type natriuretic peptide facilitates autonomic Ca 2+ entry in growth plate chondrocytes for stimulating bone growth (2022)
  • Author(s): Yuu Miyazaki#, Atsuhiko Ichimura#, Ryo Kitayama, Naoki Okamoto, Tomoki Yasue, Feng Liu, Takaaki Kawabe, Hiroki Nagatomo, Yohei Ueda, Ichiro Yamauchi, Takuro Hakata, Kazumasa Nakao, Sho Kakizawa, Miyuki Nishi, Yasuo Mori, Haruhiko Akiyama, Kazuwa Nakao, Hiroshi Takeshima
  • Journal Title: eLife Volume: 11
  • DOI: 10.7554/elife.71931
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced Ca2+ handling in thioglycolate-elicited peritoneal macrophages (2021)
  • Author(s): Liu Feng、Xu Luxin、Nishi Miyuki、Ichimura Atsuhiko、Takeshima Hiroshi
  • Journal Title: Cell Calcium Volume: 96 Pages: 102381-102381
  • DOI: 10.1016/j.ceca.2021.102381
  • Peer Reviewed / Open Access
• [Remarks] 教室ホームページ
  • URL: https://www.pharm.kyoto-u.ac.jp/biochem/
• [Remarks] 京都大学大学院薬学研究科生体分子認識学分野webページ
  • URL: https://www.pharm.kyoto-u.ac.jp/biochem/index.html
• [Remarks] 研究代表者の研究室ホームページ
  • URL: https://www.pharm.kyoto-u.ac.jp/biochem/