The epithelial sodium channel (ENaC) is expressed at the apical side of epithelial cells and is a key regulator of salt and water balance. By serving as the rate-limiting step of sodium reabsorption in the aldosterone sensitive distal nephron of the kidneys, ENaC regulates blood volume and thereby modulates blood pressure. ENaC is an obligate heterotrimeric ion channel comprised of three homologous subunits, a, b, g, and belongs to the ENaC/degenerin superfamily, known to be voltage independent, sodium selective and sensitive to the small molecule amiloride. Members of this superfamily have short intracellular N- and C-termini, two membrane-spanning a-helical segments, and a large extracellular domain (ECD). The gating of ENaC is highly unusual for an ion channel, whereby the a and g subunits are cleaved at distinct extracellular sites by proteases causing release of inhibitory peptides to activate the receptor and open the channel. Another unique property of the ENaC channel includes a high selectivity for sodium over potassium at 100:1 compared to 30-3:1 for acid sensing ion channels, another member in the same superfamily.