NHE3 is a sodium-proton exchanger expressed predominantly in the apical membrane of renal and intestinal epithelia, where it plays a key role in salt and fluid absorption and pH homeostasis. It performs these functions through the exchange of luminal sodium for cytosolic protons. Acute regulation of NHE3 function is mediated by altering the total number of exchangers in the plasma membrane as well as their individual activity. Traffic between endomembrane and plasmalemmal pools of NHE3 dictates the density of exchangers available at the cell surface. The activity of the plasmalemmal pool, however, is not fixed and can be altered by the association with modifier proteins, by post-translational alterations (such as cAMP-mediated phosphorylation) and possibly also via interaction with specific plasmalemmal phospholipids. Interestingly, association with cytoskeletal components affects both levels of regulation, tethering NHE3 molecules at the surface and altering their intrinsic activity. This paper reviews the role of proteins and lipids in the modulation of NHE3 function.
