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

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K12904
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Eating habits
• Research Institution: University 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
• Keywords: NHE3 / 消化管 / NaCl吸収

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.

Free Research Field

生理学

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。