The amiloride-sensitive epithelial sodium channel (ENaC) is a multimeric plasma membrane protein that forms a pathway for the transport of Na⁺ across a variety of epithelia, and is associated with human hypertension and PHA. Structurally, ENaC is comprised of three homologous subunits: α, β, and γ ^[1]. All three subunits are essential for transport to the membrane assembly of functional channels on the membrane. The C-terminus of each ENaC subunit contains a PPXY motif which when mutated or deleted in either the β- or γ-ENaC subunit leads to Liddle's syndrome, a human autosomal dominant form of hypertension ^[2].

Each of the subunits consists of two transmembrane helices and an extracellular loop. The amino- and carboxy-termini of all three polypeptides are located in the cytosol. The site-directed mutagenesis studies suggest that ENaC has a central ion channel located along the central symmetry axis in between the three subunits. In terms of structure, the proteins that belong to this family consist of about 510 to 920 amino acid residues. They are made of an intracellular N-terminus region followed by a transmembrane domain, a large extracellular loop, a second transmembrane segment, and a C-terminal intracellular tail ^[3].

Amiloride binding site resides on the extracellular loop of the alpha subunit of ENaC (Yellow sphere residues 443-449) and not the putative second transmembrane domain, which forms a channel pore ^[4]. Residues in ENaC (red sphere αH418A and βR388A) disrupted the response to Cl⁻, suggesting that Cl⁻ might regulate ENaC through an analogous binding site ^[5].