MOLECULAR-PROPERTIES, KINETICS AND REGULATION OF MAMMALIAN NA+/H+ EXCHANGERS

Four mammalian Na+/H+ exchangers (NHE1, NHE2, NHE3 and NHE4) have been cloned. By Northern blot analysis and by immunocytochemistry, NHE1 is the housekeeping isoform Na+/H+ exchanger. NHE2 and NHE3 are epithelial cell-specific with NHE3 having properties of the intestinal and renal brush-border membrane Na+/H+ exchanger. Pharmacologically, these Na+/H+ exchangers exhibit a wide range in amiloride sensitivity with NHE1 and NHE2 being amiloride-sensitive and NHE3 being amiloride-resistant. Kinetically, they exhibit similar Na+ and H+ kinetics. Structurally, all cloned Na+/H+ exchangers have 10-12 membrane-spanning domains and a long cytoplasmic C-terminus. Structure-function studies suggest that the membrane-spanning domains are responsible for catalyzing Na+ and H+ exchange and the C-terminus is responsible for kinase regulation of Na+/H+ exchange. Although all cloned exchangers respond to growth factor and protein kinase regulation, mechanistically, NHE1 is stimulated by a change in the affinity for intracellular H+, and NHE2 and NHE3 are regulated by a change in the V-max of exchange. Qualitatively, growth factors have only stimulatory effects on NHE1 and NHE2 but can stimulate or inhibit NHE3. In conclusion, a gene family of Na+/H+ exchangers with a diversity in amiloride sensitivity and kinase regulation has been identified. Based on the pharmacological and physiological characteristics of NHE3, it is the Na+/H+ exchanger responsible for Na+ absorption in the brush-border membranes in intestinal and renal epithelial cells.