Structure, function and regulation of the mammalian Na+/H+ antiporters

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We have studied about structure, function and regulation of the Na^-/II^+ oxchanger (NHE, SLC9 family), in terms of i) mechanism of ion transport and pH-sensing, structure-function of regulatory cofactor CHP and involvement of NHE and its related proteins in diseases. (1)Mechanism of ion transport and pH-sensing. We elucidated the existence of "Wregulatory sites" in NHE1-NHE3 by measuring the reverse mode of exchange (^<22>Na^+-efllux) and identified several critical residues in NHE1 to regulate such H+-sites. We also identified the critical region regulating volume-sensing, and recently found that dimerization may be essential for the physiological activity of NHE. (2)Structure-function of CHP. We found that CHP is an essential cofactor for the plasma membrane exchangers (NHE1-3) to support the physiological activity and the second isoform CHP2 may be involved in maintenance of high pHi in cancer cells. Recently, we solved the crystal structure of CHP2 complexed with the NHE1-fragment and discovered the molecular mechanism for tight association between CHP/NHE. (3)Involvement of NHE or its related proteins in diseases. We found that in hypertrophied cardiac muscles the Na^-/Ca^<2+> exchanger is inhibited by calcineurin which is a major signaling molecule which leads to cardiac hypertrophy.