ENaC

ENaC, or epithelial sodium channel, is a sodium-selective ion channel expressed in the apical membranes of epithelial cells in the kidney nephron, colon, sweat glands, and airway epithelium. It belongs to the ENaC/degenerin/ASIC family of ion channels. The channel functions as a heterotrimer, typically composed of α, β, and γ subunits in most tissues; a δ subunit can substitute in some species or tissues. Each subunit contains two transmembrane domains with a large extracellular loop that participates in pore formation at the interface of the three subunits.

ENaC mediates sodium uptake with low single-channel conductance and is sensitive to the diuretic amiloride. Its activity is regulated at multiple levels, including proteolytic activation and post-translational control. Proteolytic cleavage of the extracellular loops, especially the γ subunit by intracellular and extracellular proteases such as furin and prostasin, relieves an inhibitory effect and enhances channel activity. Regulation also occurs via hormonal and ubiquitin-mediated pathways: aldosterone promotes transcription and trafficking of ENaC subunits to the apical membrane, while the ubiquitin ligase NEDD4-2 tags ENaC for endocytosis; SGK1 phosphorylation of NEDD4-2 reduces this endocytosis, increasing surface expression.

Physiological roles include sodium reabsorption in the distal nephron, contributing to extracellular fluid volume and blood pressure regulation. In the airway, ENaC modulates airway surface liquid and mucociliary clearance; in the colon and sweat glands, it participates in electrolyte balance. Pathophysiology connects ENaC to disorders such as Liddle syndrome, a gain-of-function condition causing hypertension, and pseudohypoaldosteronism type 1, a salt-wasting disorder due to ENaC dysfunction.