Summary: Amiloride-sensitive sodium channel
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Epithelial sodium channel Edit Wikipedia article
|Amiloride-sensitive sodium channel|
Structure of acid-sensing ion channel 1.
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 can be argued that it is the most selective ion channel.
The apical membrane of many tight epithelia contains sodium channels that are characterised primarily by their high affinity to 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.
Location and function
ENaC is located in the apical membrane of polarized epithelial cells in particular 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 and 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.
In cells with motile cilia, ENaC is located along the entire length of the cilia indicating that ENaC functions as a regulator of osmolarity of the periciliary fluid. In contrast to ENaC, CFTR is not found on cilia. These findings contradict previous hypothesis that stated that, under normal circumstances, ENaC is downregulated by direct interaction with CFTR and that, in CF patients, CFTR cannot downregulate ENaC, causing hyper-absorption in the lungs and recurrent lung infections.
ENaC consists of three different subunits: α, β, γ. All three subunits are essential for transport to the membrane assembly of functional channels on the membrane. 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. 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.
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.
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 appear 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. 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: 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.
There are four related amiloride sensitive sodium channels:
ENaC interaction with CFTR is of 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. Nevertheless, an upregulation of CFTR does not correct the influence of high-activity ENaC. Probably other interacting proteins are necessary to maintain a functional ion homiostasis in epithelial tissue of the lung, like potassium channels, aquaporins or Na/K-ATPase.
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.
- Jasti J, Furukawa H, Gonzales EB, Gouaux E (2007). "Structure of acid-sensing ion channel 1 at 1.9 Å resolution and low pH". Nature 449 (7160): 316–322. doi:10.1038/nature06163. PMID 17882215.
- Palmer LG (1987). "Ion selectivity of epithelial Na channels". J Membr Biol 96 (2): 97–106. doi:10.1007/BF01869236. PMID 2439691.
- Garty H (1994). "Molecular properties of epithelial, amiloride-blockab le Na+ channels". FASEB J. 8 (8): 522–528. PMID 8181670.
- Le T, Saier Jr MH (1996). "Phylogenetic characterization of the epithelial Na+ channel (ENaC) family". Mol. Membr. Biol. 13 (3): 149–157. doi:10.3109/09687689609160591. PMID 8905643.
- Lazdunski M, Waldmann R, Champigny G, Bassilana F, Voilley N (1995). "Molecular cloning and functional expression of a novel amiloride-sensitive Na+ channel". J. Biol. Chem. 270 (46): 27411–27414. doi:10.1074/jbc.270.46.27411. PMID 7499195.
- Enuka, Y.; Hanukoglu, I.; Edelheit, O.; Vaknine, H.; Hanukoglu, A. (Mar 2012). "Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways.". Histochem Cell Biol 137 (3): 339–53. doi:10.1007/s00418-011-0904-1. PMID 22207244.
- Horisberger JD, Chraïbi A (2004). "Epithelial sodium channel: a ligand-gated channel?". Nephron Physiol 96 (2): p37–41. doi:10.1159/000076406. PMID 14988660.
- Loffing J, Schild L (November 2005). "Functional domains of the epithelial sodium channel". J. Am. Soc. Nephrol. 16 (11): 3175–81. doi:10.1681/ASN.2005050456. PMID 16192417.
- Edelheit, O.; Hanukoglu, I.; Dascal, N.; Hanukoglu, A. (Apr 2011). "Identification of the roles of conserved charged residues in the extracellular domain of an epithelial sodium channel (ENaC) subunit by alanine mutagenesis.". Am J Physiol Renal Physiol 300 (4): F887–97. doi:10.1152/ajprenal.00648.2010. PMID 21209000.
- Snyder PM, McDonald FJ, Stokes JB, Welsh MJ (1994). "Membrane topology of the amiloride-sensitive epithelial sodium channel". J. Biol. Chem. 269 (39): 24379–24383. PMID 7929098.
- Saxena A, Hanukoglu I, Strautnieks SS, Thompson RJ, Gardiner RM, Hanukoglu A. (1998). "Gene structure of the human amiloride-sensitive epithelial sodium channel beta subunit". Biochem. Biophys. Res. Commun. 252 (1): 208–213. doi:10.1006/bbrc.1998.9625. PMID 9813171.
- Mall M, Grubb BR, Harkema JR, O'Neal WK, Boucher RC. (2004). "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice.". Nat Med. 10 (5): 487–93. doi:10.1038/nm1028. PMID 15077107.
- Grubb BR, O'Neal WK, Ostrowski LE, Kreda SM, Button B, Boucher RC (2012). "Transgenic hCFTR expression fails to correct β-ENaC mouse lung disease.". Am J Physiol Lung Cell Mol Physiol. 15 (302(2)): L238–47. doi:10.1152/ajplung.00083.2011. PMID 22003093.
- Toczyłowska-Mamińska R, Dołowy K. (2012). "Ion transporting proteins of human bronchial epithelium.". J Cell Biochem. 113 (2): 426–32. doi:10.1002/jcb.23393.10. PMID 21975871.
- Ion Channel Diseases
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This tab holds annotation information from the InterPro database.
InterPro entry IPR001873
The apical membrane of many tight epithelia contains sodium channels that are primarily characterised by their high affinity to the diuretic blocker amiloride [PUBMED:8181670, PUBMED:8905643, PUBMED:8905643, PUBMED:7499195]. These channels mediate the first step of active sodium reabsorption essential for the maintenance of body salt and water homeostasis [PUBMED:8181670]. In vertebrates, the channels control reabsorption of sodium in kidney, colon, lung and sweat glands; they also play a role in taste perception.
Members of the epithelial Na+ channel (ENaC) family fall into four subfamilies, termed alpha, beta, gamma and delta [PUBMED:8905643]. 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 [PUBMED:7929098]: 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.
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 [PUBMED:7929098].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||membrane (GO:0016020)|
|Molecular function||sodium channel activity (GO:0005272)|
|Biological process||sodium ion transport (GO:0006814)|
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|Seed source:||Pfam-B_415 (release 3.0)|
|Number in seed:||114|
|Number in full:||2052|
|Average length of the domain:||339.30 aa|
|Average identity of full alignment:||17 %|
|Average coverage of the sequence by the domain:||78.79 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
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