Functional analysis of MG23 and MG56

• Project/Area Number: 17K01845
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Kyoto University
• Principal Investigator: Nishi Miyuki 京都大学, 薬学研究科, 特定研究員 (60183894)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: カルシウム / 骨格筋 / 小胞体 / リアノジン受容体

Outline of Final Research Achievements

Mitsugumin 23 (MG23) is a 23 kDa transmembrane protein localized to the sarcoplasmic reticulum (SR) and nuclear membranes in a variety of cells. After reconstitution into phospholipid bilayers, MG23 behaved as a voltage-dependent cation channel, permeable to both K+ and Ca2+. Under voltage-clamp conditions, Zn2+ (>2 nM) caused dysregulated RyR2 openings and also revealed that RyR2 are not the only SR Ca2+-permeable channels regulated by Zn2+. Elevating the cytosolic Zn2+ concentration to 1 nM increased the activity of the MG23. The current amplitude of the MG23 full-open state was consistent with that previously reported for RyR2 sub-conductance gating, suggesting that in heart failure in which Zn2+ levels are elevated, RyR2 do not gate in a sub-conductance state, but rather MG23-gating becomes more apparent. These data suggest that dysregulated Zn2+ homeostasis alters the function of both RyR2 and MG23 and that both ion channels play a key role in diastolic SR Zn2+ leakage.

Academic Significance and Societal Importance of the Research Achievements

心疾患による死亡は日本人の死因の第２位に上っている。心臓の正常な機能にはカルシウムの制御が必須であり、細胞内カルシウム貯蔵庫である小胞体からカルシウムを放出するリアノジン受容体はこれまで多くの研究対象となってきた。我々が提唱している、MG23は心臓の拡張期におけるカルシウム漏出を担っている、との仮設が正しいならば、心疾患の治療戦略を大きく広げることになり、学術的にも社会的にもその意義は大きい。

Research Products

• [Int'l Joint Research] University of Texas/The Ohio State University(米国)
• [Journal Article] TRIC-A Channel Maintains Store Calcium Handling by Interacting With Type 2 Ryanodine Receptor in Cardiac Muscle (2020)
  • Author(s): Zhou X, Park KH, Yamazaki D, Lin PH, Nishi M, Ma Z, Qiu L, Murayama T, Zou X, Takeshima H, Zhou J, Ma J.
  • Journal Title: Circulation Reserach Volume: 126 Issue: 4 Pages: 417-435
  • DOI: 10.1161/circresaha.119.316241
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TRPM7 channels mediate spontaneous Ca2+ fluctuations in growth plate chondrocytes that promote bone development. (2019)
  • Author(s): Qian N, Ichimura A, Takei D, Sakaguchi R, Kitani A, Nagaoka R, Tomizawa M, Miyazaki Y, Miyachi H, Numata T, Kakizawa S, Nishi M, Mori Y, Takeshima H.
  • Journal Title: Science signaling Volume: 12 Issue: 576 Pages: 4847-4847
  • DOI: 10.1126/scisignal.aaw4847
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced activity of multiple TRIC-B channels; an ER/SR mechanism to boost counterion currents. (2019)
  • Author(s): O'Brien F, Eberhardt D, Witschas K, El-Ajouz S, Iida T, Nishi M, Takeshima H, Sitsapesan R, Venturi E.
  • Journal Title: J Physiol. Volume: 印刷中 Issue: 10 Pages: 2691-2705
  • DOI: 10.1113/jp277241
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage. (2017)
  • Author(s): Reilly-O'Donnell B, Robertson GB, Karumbi A, McIntyre C, Bal W, Nishi M, Takeshima H, Stewart AJ, Pitt SJ.
  • Journal Title: J Biol Chem. Volume: 292 Issue: 32 Pages: 13361-13373
  • DOI: 10.1074/jbc.m117.781708
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dampened activity of ryanodine receptor channels in mutant skeletal muscle lacking TRIC-A. (2017)
  • Author(s): El-Ajouz S, Venturi E, Witschas K, Beech M, Wilson AD, Lindsay C, Eberhardt D, O'Brien F, Iida T, Nishi M, Takeshima H, Sitsapesan R.
  • Journal Title: J Physiol. Volume: 595 Issue: 14 Pages: 4769-4784
  • DOI: 10.1113/jp273550
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <i><b>Gm7325</b></i><b> is MyoD-dependently expressed in activated muscle satellite </b><b>cells </b> (2017)
  • Author(s): Takei D, Nishi M, Fukada S, Doi M, Okamura H, Uezumi A, Zhang L, Yoshida M, Miyazato M, Ichimura A, Takeshima H.
  • Journal Title: Biomedical Research Volume: 38 Issue: 3 Pages: 215-219
  • DOI: 10.2220/biomedres.38.215
  • NAID: 130006865614
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] TRIC-A Channel Modulates Ca2+ Homeostasis in Mitochondria (2020)
  • Author(s): Ang Li, Xuejun Li, Jianxun Yi, Xinyu Zhou, Ki Ho Park, Miyuki Nishi, Hiroshi Takeshima, Jianjie Ma, Jingsong Zhou
  • Organizer: Biophysical society annual meeting
  • Int'l Joint Research
• [Presentation] GM7325 Transcription is regulated by nyoD in activated muscle satellite cells. (2018)
  • Author(s): Takei D, Nishi M, Fukada S, Doi M, Okamura H, Uezumi A, Zhang L, Yoshida M, Miyazato M, Ichimura A, Takeshima H.
  • Organizer: 62nd annual meeting Biophysical society
  • Int'l Joint Research
• [Presentation] Spontaneous Ca2+ Fluctuations mediated by TRPM7 channels (2018)
  • Author(s): Qian N, Ichimura A, Takei D, Zhu H, Nishi M, Takeshima H
  • Organizer: 62nd annual meeting Biophysical society
  • Int'l Joint Research
• [Remarks] 京都大学大学院薬学研究科生体分子認識学分野
  • URL: http://www.pharm.kyoto-u.ac.jp/biochem/
• [Remarks] 京都大学大学院生体分子認識学分野
  • URL: http://www.pharm.kyoto-u.ac.jp/biochem/