|Sodium channel, non voltage gated 1 delta subunit|
|Symbols||; ENaCd; ENaCdelta; SCNED; dNaCh|
|External IDs||IUPHAR: GeneCards:|
|RNA expression pattern|
The SCNN1D gene encodes for the δ (delta) subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1B, and SCNN1G.
ENaC is expressed in epithelial cells and is different from the voltage-gated sodium channel that is involved in the generation of action potentials in neurons. The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1D) represents that these are NON-voltage-gated channels.
In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid. ENaC allows transfer of sodium ions across the epithelial cell membrane in so-called "tight-epithelia" that have low permeability. The flow of sodium ions across epithelia affects osmolarity of the extracellular fluid. Thus, ENaC plays a central role in the regulation of body fluid and electrolyte homeostasis and consequently affects blood pressure.
As ENaC is strongly inhibited by amiloride, it is also referred to as an "amiloride-sensitive sodium channel".
The first cDNA encoding the delta subunit of ENaC was cloned and sequenced by Waldmann et al. from human kidney mRNA.
The sequence of the SCNN1D gene was first revealed by the human genome project. SCNN1D is located in the short arm of chromosome 1 (Ensembl database code: ENSG00000162572) and starts at nucleotide 1,280,436 on the forward strand. Its length is about 11,583 bp. The gene encodes several alternative transcripts with different transcription and translation initiation sites (see Fig. 1 below). In mRNA samples from human brain, alternative splicing products have been detected, cloned and characterized.
The tissue specific expression of the δ-subunit is very different from that of the other three subunits encoded by SCNN1A, SCNN1B, and SCNN1G. While the α, β, and γ subunits are expressed mainly in the kidney tubular epithelia, the respiratory airway, the female reproductive tract, colon, salivary and sweat glands, the δ-subunit is expressed mainly in the brain, pancreas, testis and ovary.
The primary structures of all four ENaC subunits show strong similarity. Thus, these four proteins represent a family of proteins that share a common ancestor. In global alignment (meaning alignments of sequences along their entire length and not just a partial segment), the human δ subunit shares 34% identity with the α subunit and 23% identity with the β and γ subunits.
All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2. In the membrane-bound form, the TM segments are embedded in the membrane bilayer, the amino- and carboxy-terminal regions are located inside the cell, and the segment between the two TMs remains outside of the cell as the extracellular region of ENaC. This extracellular region includes about 70% of the residues of each subunit. Thus, in the membrane-bound form, the bulk of each subunit is located outside of the cell.
The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved. The chicken ASIC1 structure revealed that ASIC1 is assembled as a homotrimer of three identical subunits. The authors of the original study suggested that the ASIC1 trimer resembles a hand holding a ball. Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.
Alignment of ENaC subunit sequences with ASIC1 sequence reveals that TM1 and TM2 segments and palm domain are conserved, and the knuckle, finger and thumb domains have insertions in ENaC. Site-directed mutagenesis studies on ENaC subunits provide evidence that many basic features of the ASIC1 structural model apply to ENaC as well.
So far mutations in the delta subunit have not been associated with a specific disease.
- Hanukoglu I, Hanukoglu A (Jan 2016). "Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases.". Gene 579 (2): 95–132. doi:10.1016/j.gene.2015.12.061. PMID 26772908.
- Bourque CW (Jul 2008). "Central mechanisms of osmosensation and systemic osmoregulation". Nature Reviews. Neuroscience 9 (7): 519–31. doi:10.1038/nrn2400. PMID 18509340.
- Rossier BC, Baker ME, Studer RA (Jan 2015). "Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited". Physiological Reviews 95 (1): 297–340. doi:10.1152/physrev.00011.2014. PMID 25540145.
- Waldmann R, Champigny G, Bassilana F, Voilley N, Lazdunski M (Nov 1995). "Molecular cloning and functional expression of a novel amiloride-sensitive Na+ channel". The Journal of Biological Chemistry 270 (46): 27411–4. doi:10.1074/jbc.270.46.27411. PMID 7499195.
- Yamamura H, Ugawa S, Ueda T, Nagao M, Shimada S (Oct 2006). "A novel spliced variant of the epithelial Na+ channel delta-subunit in the human brain". Biochemical and Biophysical Research Communications 349 (1): 317–21. doi:10.1016/j.bbrc.2006.08.043. PMID 16930535.
- Giraldez T, Afonso-Oramas D, Cruz-Muros I, Garcia-Marin V, Pagel P, González-Hernández T, Alvarez de la Rosa D (Aug 2007). "Cloning and functional expression of a new epithelial sodium channel delta subunit isoform differentially expressed in neurons of the human and monkey telencephalon". Journal of Neurochemistry 102 (4): 1304–15. doi:10.1111/j.1471-4159.2007.04622.x. PMID 17472699.
- Ji HL, Zhao RZ, Chen ZX, Shetty S, Idell S, Matalon S (Dec 2012). "δ ENaC: a novel divergent amiloride-inhibitable sodium channel". American Journal of Physiology. Lung Cellular and Molecular Physiology 303 (12): L1013–26. doi:10.1152/ajplung.00206.2012. PMID 22983350.
- Giraldez T, Rojas P, Jou J, Flores C, Alvarez de la Rosa D (Aug 2012). "The epithelial sodium channel δ-subunit: new notes for an old song". American Journal of Physiology. Renal Physiology 303 (3): F328–38. doi:10.1152/ajprenal.00116.2012. PMID 22573384.
- 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". Histochemistry and Cell Biology 137 (3): 339–53. doi:10.1007/s00418-011-0904-1. PMID 22207244.
- Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC (Dec 1994). "Cell-specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry". The Journal of Cell Biology 127 (6 Pt 2): 1907–21. PMID 7806569.
- Canessa CM, Merillat AM, Rossier BC (Dec 1994). "Membrane topology of the epithelial sodium channel in intact cells". The American Journal of Physiology 267 (6 Pt 1): C1682–90. PMID 7810611.
- Jasti J, Furukawa H, Gonzales EB, Gouaux E (Sep 2007). "Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH". Nature 449 (7160): 316–23. doi:10.1038/nature06163. PMID 17882215.
- Baconguis I, Bohlen CJ, Goehring A, Julius D, Gouaux E (Feb 2014). "X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel". Cell 156 (4): 717–29. doi:10.1016/j.cell.2014.01.011. PMID 24507937.
- Biasio W, Chang T, McIntosh CJ, McDonald FJ (Feb 2004). "Identification of Murr1 as a regulator of the human delta epithelial sodium channel". The Journal of Biological Chemistry 279 (7): 5429–34. doi:10.1074/jbc.M311155200. PMID 14645214.
- Yamamura H, Ugawa S, Ueda T, Nagao M, Shimada S (Mar 2004). "Protons activate the delta-subunit of the epithelial Na+ channel in humans". The Journal of Biological Chemistry 279 (13): 12529–34. doi:10.1074/jbc.M400274200. PMID 14726523.
- Ji HL, Benos DJ (Jun 2004). "Degenerin sites mediate proton activation of deltabetagamma-epithelial sodium channel". The Journal of Biological Chemistry 279 (26): 26939–47. doi:10.1074/jbc.M401143200. PMID 15084585.
- Yamamura H, Ugawa S, Ueda T, Nagao M, Shimada S (Oct 2004). "Capsazepine is a novel activator of the delta subunit of the human epithelial Na+ channel". The Journal of Biological Chemistry 279 (43): 44483–9. doi:10.1074/jbc.M408929200. PMID 15308635.
- Ji HL, Su XF, Kedar S, Li J, Barbry P, Smith PR, Matalon S, Benos DJ (Mar 2006). "Delta-subunit confers novel biophysical features to alpha beta gamma-human epithelial sodium channel (ENaC) via a physical interaction". The Journal of Biological Chemistry 281 (12): 8233–41. doi:10.1074/jbc.M512293200. PMID 16423824.