Mammalian Na⁺/H⁺ exchanger gene family: Structure and function studies

Na⁺/H⁺ exchangers are integral plasma membrane proteins that exchange extracellular Na⁺ for intracellular H⁺ with a stoichiometry of one for one. They are inhibitable by the diuretic amiloride and have multiple cellular functions, including intracellular pH homeostasis, cell volume control, and electroneutral NaCl absorption in epithelia. The presence of multiple forms of the exchangers was demonstrated by the recent cloning of four mammalian Na⁺/H⁺ exchangers, NHE1, NHE2, NHE3, and NHE4. All of these cloned Na⁺/H⁺ exchangers have 10-12 putative transmembrane helixes and a long cytoplasmic carboxyl domain. Despite the structural similarity, these Na⁺/H⁺ exchanger isoforms differ in their tissue distribution, kinetic characteristics, and response to external stimuli. The present review deals with the recent developments in the molecular identification of the Na⁺/H⁺ exchanger gene family, the functional characteristics, and the short-term regulation of Na⁺/H⁺ exchange at molecular and cellular levels.