Na+/H+ exchangers.

Tightly coupled exchange of Na(+) for H(+) occurs across the surface membrane of virtually all living cells. For years, the underlying molecular entity was unknown and the full physiological significance of the exchange process was not appreciated, but much knowledge has been gained in the last two decades. We now realize that, unlike most of the other transporters that specialize in supporting one specific function, Na(+)/H(+) exchangers (NHE) participate in a remarkable assortment of physiological processes, ranging from pH homeostasis and epithelial salt transport, to systemic and cellular volume regulation. In parallel, we have learned a great deal about the biochemistry and molecular biology of Na(+)/H(+) exchange. Indeed, it has now become apparent that exchange is mediated not by one, but by a diverse family of related yet distinct carriers (antiporters) sometimes present in different cell types and located in various intracellular compartments. Each one of these has unique structural features that dictate its functional role and mode of regulation. The biological relevance of Na(+)/H(+) exchange is emphasized by its evolutionary conservation; analogous exchangers are present from bacteria to man. Because of its wide distribution and versatile function, Na(+)/H(+) exchange has attracted an enormous amount of interest and therefore generated a vast literature. The vastness and complexity of the field has been compounded by the multiplicity of NHE isoforms. For reasons of space and in the spirit of this series, this overview is restricted to the family of mammalian NHEs.