Molecular physiology of vertebrate Na+/H+ exchangers

This review describes recent progress concerning the molecular aspects of the Na+/H+ exchanger. The Na+/H+ exchanger is an important regulator for intracellular pH, cell volume, and transepithelial Na+ transport. It exists in virtually all cells with cell type-dependent pattern of isoform expression, and it is regulated in response to a variety of extracellular stimuli, among them not only agonists such as growth factors and hormones but also mechanical stimuli such as osmotic stress and cell spreading. Thus this transporter is also an excellent model to study the signal transduction. Since the first molecular cloning of the Na+/H+ exchanger, detailed studies revealed many interesting features of this transporter. At present, at least five different isoforms of the Na+/H+ exchanger are known. These isoforms differ in tissue localization, sensitivity of inhibitors, and mode of transcriptional and posttranscriptional regulation, allowing them to participate in different physiological processes. We have only started to understand an intriguing mechanism underlying these functional differences among the exchanger isoforms. Because the Na+/H+ exchanger is relatively simple in terms of its kinetic features, e.g., a simple 1:1 stoichiometry of Na+ and H+ and no input of metabolic energy such as ATP hydrolysis, the study of its structural and mechanistic aspects would also serve as a good model to understand the general mechanism of various ion transporters.