Na+/H+ antiport is a major determinant of intracellular pH (pHi) and also plays an important role in the maintenance of cellular volume. Na+/H+ exchange through NHE-1, the ubiquitous isoform of the antiporter, is accelerated by cytosolic acidification and also by osmotically induced cell shrinking, thereby promoting recovery of the physiological pHi and volume, respectively. Although hydrolysis of ATP is not required for transport of ions through the antiporter, metabolic depletion exerts a marked inhibitory effect. Depletion of ATP also prevents osmotic activation and volume regulation. Contrary to earlier suggestions, however, changes in the phosphorylation state of the antiporter itself are not involved in the effects of either metabolic depletion or osmotic stimulation. Nevertheless, the cytosolic carboxy-terminal segment of the antiporter, which contains the major phosphorylation sites, is essential for the ATP dependence as well as for osmotic activation. It is conceivable that this domain interacts with ancillary phosphorylated or nucleotide-binding proteins, with the cytoskeleton and/or with specific phospholipids, which modulate the rate of transport. Nucleotide dependence and osmotic sensitivity have been compared in three different isoforms of the antiporter, heterologously expressed in fibroblastic cells. Like NHE-1, NHE-2 and NHE-3 were severely inhibited by depletion of ATP. In contrast, whereas NHE-2 was stimulated by osmotic shrinkage, NHE-3 was inhibited. The possible physiological significance of the ATP-dependence and osmotic responsiveness of the antiporter isoforms is discussed.

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