Functional analysis of MG23 and MG56

2019 Fiscal Year Final Research Report

• 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
• Keywords: カルシウム / 骨格筋 / 小胞体

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.

Free Research Field

生化学

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。