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Elucidation of transport mechanism of NHE3 for novel therapeutic target in chronic kidney disease.

Research Project

Project/Area Number 17K12904
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Eating habits
Research InstitutionUniversity of Shizuoka

Principal Investigator

Ishizuka Noriko  静岡県立大学, 食品栄養科学部, 助教 (30440283)

Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsNHE3 / 消化管 / NaCl吸収 / 輸送体 / 食塩
Outline of Final Research Achievements

Transport activity of intestinal Na/H exchanger 3 isoform (NHE3) is sensitive to intracellular pH (pHi). At resting pHi, a large fraction of transporters resides in an inactive state. When the H+ concentration of the cytosol rises, the transporters are converted into an active state. We have previously shown that NHE3 is slowly activated over the course of minutes, implying involvement of a conformational change of NHE3 such as dimerization in heterogenous expression systems. Under physiological conditions, NHE3 is thought to be coupled with other transporters in a concerted manner. To gain insight into the activation mechanism of NHE3, we used the NHE3 specific inhibitor tenapanor, which has a symmetrical structure with two proposed binding sites. Our results suggested that tenapanor may irreversibly bind to NHE3 and recognize the different NHE3 transport modes.

Academic Significance and Societal Importance of the Research Achievements

Na+/ H+交換輸送体(NHE)3はNa+吸収と交換にH+を細胞外に排出している。このためNHE3は、Na+吸収と同時に、細胞内pH調節にも関与する。本研究ではNHE3阻害剤を用いて、NHE3の機能活性をNaCl吸収機能(Cl-輸送体とカップルする)とH+排出機能(H+依存性ペプチド吸収とカップルする)として評価した。NHE3阻害剤は前者を大きく抑制しないが、後者を強く抑制した。これはNHE3とカップルする輸送体によりNHE3阻害剤の作用機構が異なることが理由として考えられた。研究成果は新たな腸管からのNa+吸収抑制機序の発見に繋がる可能性が示唆された。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (4 results)

All 2019 2018

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (3 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Luminal Na+ homeostasis has an important role in intestinal peptide absorption in vivo.2018

    • Author(s)
      Ishizuka N, Nakayama M, Watanabe M, Tajima H, Yamauchi Y, Ikari A, Hayashi H
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol.

      Volume: 315 Issue: 5 Pages: 799-809

    • DOI

      10.1152/ajpgi.00099.2018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] Oligomerization of Na+/H+ exchanger isoform 3 (NHE3) and its role in the transport mechanism2019

    • Author(s)
      Noriko Ishizuka, Shino Koido and Hisayoshi Hayashi
    • Organizer
      9th Federation of the Asian and Oceanian Physiological Societies Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 消化管Na+吸収輸送体NHE3の活性化機序の検討2018

    • Author(s)
      石塚 典子、林 久由
    • Organizer
      第49回日本消化吸収学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 小腸ペプチド吸収における管腔Na恒常性の重要性2018

    • Author(s)
      石塚 典子、林 久由
    • Organizer
      第49回日本消化吸収学会総会
    • Related Report
      2018 Annual Research Report

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Published: 2017-04-28   Modified: 2020-03-30  

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