A multi-hierarchical approach uncovers the hidden physiological substrates of membrane transport proteins

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H03365
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Nagamori Shushi 東京慈恵会医科大学, 医学部, 教授 (90467572)
• Co-Investigator(Kenkyū-buntansha): Wiriyasermkul Pattama 東京慈恵会医科大学, 医学部, 助教 (80825836) ; 笹部 潤平 慶應義塾大学, 医学部(信濃町), 講師 (10398612) ; 西山 賢一 岩手大学, 農学部, 教授 (80291334)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: D-アミノ酸 / トランスポーター / マルチオミクス / 腎臓 / D-セリン / 多階層

Outline of Final Research Achievements

Many transporters are orphans with unknown physiological functions, leaving many nutrient transport systems unclear. While amino acid transport research focuses on L-amino acids, trace amounts of D-amino acids, such as D-serine, also exist and play significant roles. However, D-serine transport mechanisms are largely unknown. This study used a "multi-hierarchical approach" integrating multi-omics analyses and various transport function systems, from synthetic cell-free to ex vivo and in vivo models, to identify renal D-serine transport systems. Two systems were identified: ASCT2 and the monocarboxylate transporters (SMCTs). These systems are physiologically complementary, with ASCT2 playing a primary role under pathological conditions. The findings highlight the importance of non-canonical substrate transport and provide a framework for investigating multiple transport systems of various trace micromolecules.

Free Research Field

生化学、膜輸送体、プロテオミクス

Academic Significance and Societal Importance of the Research Achievements

輸送システムの生理的基質を明らかにする「多階層的アプローチ」を開発し、D-セリンがモノカルボン酸輸送体の隠れた生理的基質であることが見いだされた。本成果は、D-セリンの腎機能マーカーとしての機序解明に繋がり、さらに生体内で重要な働きをする様々な微量分子の複雑な輸送システムを明らかにする手法を提供するものである。