抄録
The Na+/H+ exchanger (NHE, SLC9 family) is an ion transporter that regulates the ionic homeostasis such as intracellular pH (pHi), Na+ concentration and cell volume. Such physiological function is intimately linked to the remarkable propertie of NHE, i.e., it is rapidly activated in response to a variety of extracellular stimuli such as hormones, growth factors and mechanical stressors. In recent years, we have focused on several essential factors for function of the ubiquitous isoform NHE1. We obtained evidence that at least three processes are necessary: 1) interaction of multiple protons with the regulatory "pH-sensor" sites in the cytoplasmic side of NHE1, 2) homo-dimerization of NHE1 and 3) interaction with calcineurin B-homologous protein CHP at the juxtamembrane cytoplasmic region of NHE1. CHP is one of EF-hand Ca2+ binding proteins and now at least three isoforms are known. We recently suggested that CHP2 is almost exclusively expressed in cancer cells and may be involved in maintenance of high pHi in these cells, while CHP1 is ubiquitously expressed in virtually all tissues. More recently, we determined the crystal structure of CHP2 complexed with the cytosolic region (aa 503-545) of NHE1 at 2.7 Å and clarified the molecular basis for producing the target specificity of related Ca2+ binding proteins at atomic level. In this symposium, we will particularly focus on the crystal structure of the CHP/NHE1-peptide complex and the mechanism of pHi regulation by NHE1/CHP complex. [J Physiol Sci. 2007;57 Suppl:S42]
