SLC9A3

SLC9A3, or solute carrier family 9 member 3, encodes the epithelial sodium/hydrogen exchanger 3 (NHE3). It is a membrane transporter expressed primarily on the apical surfaces of epithelial cells in the kidney proximal tubule and the small intestine, where it contributes to the reabsorption of sodium and the regulation of acid–base balance.

Functionally, NHE3 exchanges extracellular Na+ for intracellular H+, playing a major role in sodium and fluid absorption. In the kidney, it supports proximal tubule Na+ reabsorption, while in the intestine it participates in dietary Na+ uptake and concomitant water absorption. Through this activity, NHE3 influences extracellular fluid volume, blood pressure, and bicarbonate handling.

Regulation of SLC9A3/NHE3 is complex and context dependent. Hormonal signals such as angiotensin II and glucocorticoids can promote membrane trafficking and activity, whereas counteracting signals that raise intracellular cAMP or Ca2+ can inhibit activity or trigger endocytosis. Protein interactions with scaffolding and cytoskeletal partners, notably NHERF1 and NHERF2 (and ezrin), anchor NHE3 at the apical membrane and modulate its localization and stability. Post-translational modifications, including phosphorylation, also affect its activity.

Genetic and clinical aspects: Loss-of-function mutations in SLC9A3 can cause congenital sodium diarrhea, a rare disorder characterized by excessive intestinal Na+ loss and watery stools with electrolyte disturbances. Variants of SLC9A3 may influence intestinal Na+ absorption and fluid balance, and research continues into their roles in broader enteric and renal physiology and disease contexts. In research settings, NHE3 activity is sometimes studied using specific inhibitors such as S3226.