| Amiloride-sensitive sodium channel | |||||||||
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| Structure of acid-sensing ion channel 1.[1] | |||||||||
| Identifiers | |||||||||
| Symbol | ASC | ||||||||
| Pfam | PF00858 | ||||||||
| InterPro | IPR001873 | ||||||||
| PROSITE | PDOC00926 | ||||||||
| SCOP | 2qts | ||||||||
| TCDB | 1.A.6 | ||||||||
| OPM family | 202 | ||||||||
| OPM protein | 2qts | ||||||||
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The epithelial sodium channel (short: ENaC, also: sodium channel non-neuronal 1 (SCNN1) or amiloride sensitive sodium channel (ASSC)) is a membrane-bound ion-channel that is permeable for Li+-ions, protons and especially Na+-ions. It is a constitutively active ion-channel. It is arguably the most selective ion channel.[2]
The apical membrane of many tight epithelia contains sodium channels that are primarily characterised by their high affinity to the diuretic blocker amiloride.[3][4][4][5] These channels mediate the first step of active sodium reabsorption essential for the maintenance of body salt and water homeostasis.[3] In vertebrates, the channels control reabsorption of sodium in kidney, colon, lung and sweat glands; they also play a role in taste perception.
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ENaC is located in the apical membrane of polarized epithelial cells particularly in the kidney (primarily in the collecting tubules), the lung and the colon. It is involved in the transepithelial Na+-ion transport, which it accomplishes together with the Na+/K+-ATPase.
It plays a major role in the Na+- and K+-ion homeostasis of blood, epithelia and extraepithelial fluids by resorption of Na+-ions. The activity of ENaC in 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.
ENaC can furthermore be found in taste receptor cells, where it plays an important role in salt taste 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.
It has been suggested that it may be a ligand-gated ion channel.[6]
ENaC consists of three different subunits: α, β, γ.[7] The stoichiometry of these subunits is still to be verified, but ENaC is very likely to be a heterotrimeric protein like the recently analyzed acid-sensing ion channel 1 (ASIC1), which belongs to the same family.[1] Each of the subunits consists of two transmembrane helices and an extracellular loop. The amino- and carboxy-termini of all polypeptides are located in the cytosol.
Structurally, 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.[8]
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. Such δ, β, γ-ENaC appears in pancreas, testes and ovaries. Their function is yet unknown.
Members of the epithelial Na+ channel (ENaC) family fall into four subfamilies, termed alpha, beta, gamma and delta.[4] The proteins exhibit the same apparent topology, each with two transmembrane (TM) spanning segments, separated by a large extracellular loop. In most ENaC proteins studied to date, the extracellular domains are highly conserved and contain numerous cysteine residues, with flanking C-terminal amphipathic TM regions, postulated to contribute to the formation of the hydrophilic pores of the oligomeric channel protein complexes. It is thought that the well-conserved extracellular domains serve as receptors to control the activities of the channels.
Vertebrate ENaC proteins are similar to degenerins of Caenorhabditis elegans[8]: deg-1, del-1, mec-4, mec-10 and unc-8. These proteins can be mutated to cause neuronal degradation, and are also thought to form sodium channels.
The exon–intron architecture of the three genes encoding the three subunits of ENaC have remained highly conserved despite the divergence of their sequences.[9]
There are four related amiloride sensitive sodium channels:
ENaC interaction with CFTR is arguably of the most important pathophysiological relevance in cystic fibrosis. CFTR is a transmembrane channel responsible for chloride transport and defects in this protein cause cystic fibrosis, partly through upregulation of the ENaC channel in the absence of functional CFTR.
In the airways, CFTR allows for the secretion of chloride, and sodium ions and water follow passively. 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. This results in the deposition of thick, dehydrated mucus, which collects in the respiratory tract, interfering with gas exchange and allowing for the collection of bacteria.
In sweat glands, CFTR is responsible for the reabsorption of chloride in the sweat duct. Sodium ions follow passively through ENaC as a result of the electrochemical gradient caused by chloride flow. This reduces salt and water loss. In the absence of chloride flow in cystic fibrosis, sodium ions do not flow through ENaC, leading to greater salt and water loss. (This is true despite upregulation of the ENaC channel, as flow in the sweat ducts is limited by the electrochemical gradient set up by chloride flow through CFTR.) As such, patients' skin tastes salty, and this is commonly used to help diagnose the disease, both in the past and today by modern electrical tests.
The β and γ subunits are associated with Liddle's syndrome.[10]
Amiloride and triamterene are potassium-sparing diuretics which act as epithelial sodium channel blockers.
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This article incorporates text from the public domain Pfam and InterPro IPR001873