Epithelial sodium channel

The epithelial sodium channel (short: ENaC, also: amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to the ions of sodium (Na+) and that is assembled as a heterotrimer composed of three homologous subunits α or δ, β, and γ, These subunits are encoded by four genes: SCNN1A, SCNN1B, SCNN1G, and SCNN1D. It is involved primarily in the reabsorption of sodium ions at the collecting ducts of the kidney's nephrons. The epithelial sodium channel (short: ENaC, also: amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to the ions of sodium (Na+) and that is assembled as a heterotrimer composed of three homologous subunits α or δ, β, and γ, These subunits are encoded by four genes: SCNN1A, SCNN1B, SCNN1G, and SCNN1D. It is involved primarily in the reabsorption of sodium ions at the collecting ducts of the kidney's nephrons. The apical membranes of many tight epithelia contain sodium channels that are characterized primarily by their high affinity for the diuretic blocker amiloride. These channels mediate the first step of active sodium reabsorption essential for the maintenance of body salt and water homeostasis. In vertebrates, the channels control reabsorption of sodium in kidney, colon, lung and sweat glands; they also play a role in taste perception. The epithelial sodium channels are structurally and probably evolutionary related to P2X purinoreceptors, pain receptors that activate when they detect ATP. 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, the male and female reproductive tracts and the colon. Epithelial sodium channels facilitate Na⁺ reabsorption across the apical membranes of epithelia in the distal nephron, respiratory and reproductive tracts and exocrine glands. Since Na⁺ ion concentration is a major determinant of extracellular fluid osmolarity, changes in Na⁺ concentration affect the movement of fluids and consequently fluid volume and blood pressure. The activity of ENaC in the colon and kidney is modulated by the mineralcorticoid aldosterone. It can be blocked by either triamterene or amiloride, which are used medically to serve as diuretics. In the kidney, it is inhibited by atrial natriuretic peptide, causing natriuresis and diuresis. Epithelial Na+ channels (ENaCs) in the brain play a significant role in the regulation of blood pressure. Vasopressin (VP) neurons play a pivotal role in coordinating neuroendocrine and autonomic responses to maintain cardiovascular homeostasis. High dietary salt intake caused an increase in the expression and activity of ENaC which resulted in the steady state depolarization of VP neurons. This is one of the mechanisms underlying how dietary salt intake affects the activity of VP neurons via ENaC activity. ENaC channels in the brain are involved in blood pressure response to dietary sodium. High-resolution immunofluorescence studies revealed that in the respiratory tract and the female reproductive tract, ENaC is located along the entire length of cilia that cover the surface of multi-ciliated cells. Hence, in these epithelia with motile cilia, ENaC functions as a regulator of the osmolarity of the periciliary fluid, and its function is essential to maintain fluid volume at a depth necessary for the motility of the cilia. In the respiratory tract this movement is essential for clearing mucosal surface, and in the female reproductive tract, motility of the cilia is essential for the movement of oocytes. In contrast to ENaC, CFTR that regulates chloride ion transport is not found on cilia. These findings contradict a previous hypothesis that ENaC is downregulated by direct interaction with CFTR. In patients with cystic fibrosis (CF), CFTR cannot downregulate ENaC, causing hyper-absorption in the lungs and recurrent lung infections. It has been suggested that it may be a ligand-gated ion channel. In the skin epidermal layers, ENaC is expressed in the keratinocytes, sebaceous glands, and smooth muscle cells. In these cells ENaC is mostly located in the cytoplasm. In the eccrine sweat glands, ENaC is predominantly located in the apical membrane facing the lumen of the sweat ducts. The major function of ENaC in these ducts is the re-uptake of Na⁺ ions that are excreted in sweat. In patients with ENaC mutations that cause systemic pseudohypoaldosteronism type I, the patients can lose a significant amount of Na⁺ ions, especially under hot climates. ENaC is also found in taste receptors, where it plays an important role in saltiness perception. 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.