Summary

Transport activity of Na⁺/H⁺ exchanger 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 intestinal Na⁺/H+ exchanger 3 isoform (NHE3) is slowly activated over the course of minutes, implying involvement of a conformational change of NHE3. Recently, some NHE3 specific inhibitors have been developed to treat sodium-fluid imbalance diseases. However, the action of these inhibitors on NHE3 is not fully elucidated. To gain insight into the inhibition mechanism of NHE3 inhibitors, we used exogenous NHE3 expressing cells and mouse intestine. Our results suggested that tenapanor, which has a symmetrical structure with two proposed binding sites, may irreversibly bind to NHE3 and recognize the different NHE3 transport modes