Multiple Modes of Regulation of Na+/H+ Exchangers

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Abstract
Mammalian Na+/H+ exchangers (NHE) mediate electroneutral countertransport of H+ for Na+ across the plasmalemmal and organellar membranes. They contribute to cellular and organellar pH and volume regulation and transepithelial Na+ transport. The aim of this review is to illustrate the complex regulation of these transporters by focusing on the multiple mechanisms controlling the epithelial isoform, NHE3. A variety of agents and conditions (e.g., hormones, growth factors, cellular pH, and medium osmolarity) act in concert to achieve short‐term and long‐term regulation of this isoform. The underlying mechanism involves changes in the number of transporters on the cell surface and/or altered activity of the individual exchangers due to allosteric activation by intracellular protons, phosphorylation and interaction with accessory proteins and the cytoskeleton. A similar regulatory versatility probably applies to other NHE isoforms, and the lessons learned from studying members of the NHE family could serve as a useful reference when exploring the modes and levels of regulation of other transporters.