InterPro domain: IPR018422

Sodium proton exchangers (NHEs) constitute a large family of integral membrane protein transporters that are responsible for the counter-transport of protons and sodium ions across lipid bilayers [ 1 , 2 ]. These proteins are found in organisms across all domains of life. In archaea, bacteria, yeast and plants, these exchangers provide increased salt tolerance by removing sodium in exchanger for extracellular protons. In mammals they participate in the regulation of cell pH, volume, and intracellular sodium concentration, as well as for the reabsorption of NaCl across renal, intestinal, and other epithelia [ 3 , 4 , 5 , 6 ]. Human NHE is also involved in heart disease, cell growth and in cell differentiation [ 7 ]. The removal of intracellular protons in exchange for extracellular sodium effectively eliminates excess acid from actively metabolising cells. In mammalian cells, NHE activity is found in both the plasma membrane and inner mitochondrial membrane. To date, nine mammalian isoforms have been identified (designated NHE1-NHE9) [ 8 , 9 ]. These exchangers are highly-regulated (glyco)phosphoproteins, which, based on their primary structure, appear to contain 10-12 membrane-spanning regions (M) at the N terminus and a large cytoplasmic region at the C terminus. The transmembrane regions M3-M12 share identity with other members of the family. The M6 and M7 regions are highly conserved. Thus, this is thought to be the region that is involved in the transport of sodium and hydrogen ions. The cytoplasmic region has little similarity throughout the family. There is some evidence that the exchangers may exist in the cell membrane as homodimers, but little is currently known about the mechanism of their antiport [ 10 ].

This entry represents the cation:proton antiporter family 1 (CPA1), which includes Na+/H+ exchangers, K+/H+ exchangers and Na+(K+,Li+,Rb+)/H+ exchangers.

1. The Na+/H+ exchanger gene family. J. Nephrol. 15 Suppl 5, S3-21
2. Multiple modes of regulation of Na+/H+ exchangers. Ann. N. Y. Acad. Sci. 976, 248-58
3. Na+/H+ exchangers and the regulation of volume. Semin. Nephrol. 187, 159-67
4. Na+/H+ exchangers in renal regulation of acid-base balance. J. Exp. Bot. 26, 334-44
5. Alkali cation exchangers: roles in cellular homeostasis and stress tolerance. Seikagaku 57, 1181-99
6. [Structure function and regulation of the mammalian Na+/H+ exchangers] Can. J. Physiol. Pharmacol. 72, 1329-34
7. Physiological role and regulation of the Na+/H+ exchanger. null 84, 1081-95
8. Na+/H+ exchangers of mammalian cells. J. Biol. Chem. 272, 22373-6
9. Identification of a mitochondrial Na+/H+ exchanger. J. Biol. Chem. 273, 6951-9
10. Comparative molecular analysis of Na+/H+ exchangers: a unified model for Na+/H+ antiport? FEBS Lett. 424, 1-5