Molecular physiology of intestinal Na⁺/H⁺ exchange

The sodium/hydrogen exchange (NHE) gene family plays an integral role in neutral sodium absorption in the mammalian intestine. The NHE gene family is comprised of nine members that are categorized by cellular localization (i.e., plasma membrane or intracellular). In the gastrointestinal (GI) tract of multiple species, there are resident plasma membrane isoforms including NHE1 (basolateral) and NHE2 (apical), recycling isoforms (NHE3), as well as intracellular isoforms (NHE6, 7,9). NHE3 recycles between the endosomal compartment and the apical plasma membrane and functions in both locations. NHE3 regulation occurs during normal digestive processes and is often inhibited in diarrheal diseases. The C terminus of NHE3 binds multiple regulatory proteins to form large protein complexes that are involved in regulation of NHE3 trafficking to and from the plasma membrane, turnover number, and protein phosphorylation. NHE1 and NHE2 are not regulated by trafficking. NHE1 interacts with multiple regulatory proteins that affect phosphorylation; however, whether NHE1 exists in large multi-protein complexes is unknown. Although intestinal and colonic sodium absorption appear to involve at least NHE2 and NHE3, future studies are necessary to more accurately define their relative contributions to sodium absorption during human digestion and in pathophysiological conditions.