In addition to being implicated in diseases where fluid balance across epithelial membranes is perturbed, including pulmonary edema, cystic fibrosis, COPD and COVID-19, proteolyzed forms of ENaC function as the human salt taste receptor.

[3] The apical membranes of many tight epithelia contain sodium channels that are characterized primarily by their high affinity for the diuretic blocker amiloride.

[2][4][5][6] These channels mediate the first step of active sodium reabsorption essential for the maintenance of body salt and water homeostasis.

[4] In vertebrates, the channels control reabsorption of sodium in kidney, colon, lung and sweat glands; they also play a role in taste perception.

ENaC is located in the apical membrane of polarized epithelial cells in particular in the kidney (primarily in the collecting tubule), the lung, the skin,[7] the male and female reproductive tracts and the colon.

[2][8][9] Epithelial sodium channels facilitate Na⁺ reabsorption across the apical membranes of epithelia in the distal nephron, respiratory and reproductive tracts and exocrine glands.

[11] Vasopressin (VP) neurons play a pivotal role in coordinating neuroendocrine and autonomic responses to maintain cardiovascular homeostasis.

High dietary salt intake causes an increase in the expression and activity of ENaC which results in the steady state depolarization of VP neurons.

Homologues of acid-sensing ion channels (ASIC) of the ENaC family mediate touch sensation in invertebrates (including the model organism C. elegans), and had also been thought responsible for mechanoactivated membrane currents in higher animals.

[10]: 677  In rodents, virtually the entire salt taste is mediated by ENaC, whereas it seems to play a less significant role in humans: About 20 percent can be accredited to the epithelial sodium channel.

This role was first confirmed using human sensory studies to evaluate the effect of 4-propylphenyl 2-furoate on the perception of the salty taste of table salt, sodium chloride (NaCl).

[22] In addition there is a fourth, so-called δ-subunit, that shares considerable sequence similarity with the α-subunit and can form a functional ion-channel together with the β- and γ-subunits.

[25] There are four related amiloride sensitive sodium channels: ENaC interaction with CFTR is of important pathophysiological relevance in cystic fibrosis.

However, in the absence of functional CFTR, the ENaC channel is upregulated, and further decreases salt and water secretion by reabsorbing sodium ions.

As such, the respiratory complications in cystic fibrosis are not solely caused by the lack of chloride secretion but instead by the increase in sodium and water reabsorption.

[27] Probably other interacting proteins are necessary to maintain a functional ion homeostasis in epithelial tissue of the lung, like potassium channels, aquaporins or Na/K-ATPase.