[5] ENaC is expressed in epithelial cells and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons.

[6] ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability.

Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.

The first cDNA encoding the gamma subunit of ENaC was cloned and sequenced by Canessa et al. from rat mRNA.

[8] A year later, two independent groups reported the cDNA sequences of the beta- and gamma-subunits of the human ENaC.

The three ENaC subunits encoded by SCNN1A, SCNN1B, and SCNN1G are commonly expressed in tight epithelia that have low water permeability.

The major organs where ENaC is expressed include parts of the kidney tubular epithelia,[5][7][16] the respiratory airway,[17] the female reproductive tract,[17] colon, salivary and sweat glands.

[16] The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.

[5] In the carboxy terminus of three ENaC subunits, (α, β and γ) there is a special conserved consensus sequence PPPXYXXL that is called the PY motif.

Liddle syndrome is inherited as an autosomal dominant disease with a phenotype that includes early onset hypertension, metabolic alkalosis and low levels of plasma renin activity and mineralocorticoid hormone aldosterone.

In the absence of a recognizable PY motif, ubiquitin-protein ligase Nedd4-2 cannot bind to the ENaC subunit and hence cannot attach a ubiquitin to it.