Sodium-hydrogen exchanger 3 (NHE3) (NHE3)

Sodium-hydrogen exchanger 3 (NHE3), encoded by the SLC9A3 gene, is a transmembrane protein primarily localized to the apical brush-border membrane of the small intestine and the proximal tubule of the kidney (UniProt: P48764). Its principal biological function is the electroneutral exchange of extracellular sodium ions for intracellular protons, which serves as the major pathway for sodium and fluid absorption in the gut (PubMed: 25624332). In clinical practice, NHE3 is a significant therapeutic target for managing gastrointestinal and renal conditions. Specifically, the inhibition of intestinal NHE3 by drugs like tenapanor prevents sodium uptake, thereby increasing luminal fluid and improving symptoms of irritable bowel syndrome with constipation (IBS-C) (FDA: Ibsrela). Additionally, NHE3 inhibition has been shown to reduce systemic phosphate levels in patients with chronic kidney disease by modulating paracellular permeability (PubMed: 29038204). Beyond its role in fluid balance, genetic mutations in SLC9A3 are linked to congenital sodium diarrhea, underscoring its essential role in maintaining electrolyte homeostasis (PubMed: 24403053).

Other names

SLC9A3Sodium-hydrogen exchanger 3NHE-3Solute carrier family 9 member 3Sodium-hydrogen antiporter 3Sodium-hydrogen antiporter in intestinal brush-border membranes

Tenapanor inhibits NHE3, which reduces sodium absorption from the small intestine and colon. This leads to an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and softens stool consistency (PMID: 28114211). Additionally, NHE3 inhibition reduces phosphate absorption by decreasing paracellular permeability to phosphate ions (PMID: 29038204).