SLC9A3 Gene - Sodium/Hydrogen Exchanger 3 (NHE3) | Function, Mutations & Clinical Significance

SLC9A3 encodes the sodium/hydrogen exchanger 3 (NHE3), an electroneutral transporter that mediates the exchange of extracellular sodium for intracellular hydrogen ions across the plasma membrane. NHE3 is predominantly expressed in the apical membrane of renal proximal tubule cells and intestinal epithelial cells, where it plays a critical role in sodium reabsorption, acid-base balance, and fluid volume homeostasis. Loss-of-function mutations cause congenital sodium diarrhea (OMIM #270420).

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Renal reabsorption of sodium (Reactome R-HSA-549127)

• Ion transport by P-type ATPases (Reactome R-HSA-936837)

• Transport of inorganic cations/anions (Reactome R-HSA-425393)

NHE3 (UniProt P48764) is a 10-12 transmembrane domain protein of 832 amino acids. It localizes to the apical membrane of renal proximal tubule and intestinal epithelial cells. The protein functions as an electroneutral Na+/H+ antiporter, coupling sodium influx to proton efflux. Its activity is regulated by phosphorylation, trafficking, and interactions with scaffolding proteins such as NHERF1/2. NHE3 is essential for sodium and bicarbonate reabsorption in the kidney and for sodium absorption in the gut.