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SCNN1D

This article was updated by an external expert under a dual publication model. The corresponding peer-reviewed article was published in the journal Gene. Click to view.
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SCNN1D
Identifiers
AliasesSCNN1D,ENaCd, ENaCdelta, SCNED, dNaCh, sodium channel epithelial 1 delta subunit, sodium channel epithelial 1 subunit delta
External IDsOMIM:601328;HomoloGene:48152;GeneCards:SCNN1D;OMA:SCNN1D - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6339

n/a

Ensembl

ENSG00000162572

n/a

UniProt

P51172

n/a

RefSeq (mRNA)

NM_001130413
NM_002978

n/a

RefSeq (protein)

NP_001123885

n/a

Location (UCSC)Chr 1: 1.28 – 1.29 Mbn/a
PubMedsearch[2]n/a
Wikidata
View/Edit Human

TheSCNN1Dgene encodes for the δ (delta) subunit of the epithelial sodium channelENaCin vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ.[3]The other ENAC subunits are encoded bySCNN1A,SCNN1B,andSCNN1G.

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.[4]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.[5]

As ENaC is strongly inhibited byamiloride,it is also referred to as an "amiloride-sensitive sodium channel".

History

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The first cDNA encoding the delta subunit of ENaC was cloned and sequenced by Waldmann et al. from human kidney mRNA.[6]

Gene structure

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Exon-intron structure of the major transcript of humanSCNN1D.The serial number of each transcript is shown above the transcript. Clicking on the figure will direct the reader to the list of transcripts in the Ensembl database.

The sequence of theSCNN1Dgene was first revealed by the Human Genome Project.SCNN1Dis 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. In mRNA samples from human brain, alternative splicing products have been detected, cloned and characterized.[7][8] TheSCNN1Dgene is found in most vertebrates,[3]but the gene has been lost in the mouse and rat genomes.[9][10]

Tissue-specific expression

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The tissue specific expression of the δ-subunit is very different from that of the other three subunits encoded bySCNN1A,SCNN1B,andSCNN1G.While the α, β, and γ subunits are expressed mainly in the kidney tubular epithelia, the respiratory airway,[11]the female reproductive tract,[11]colon, salivary and sweat glands,[12]the δ-subunit is expressed mainly in the brain, pancreas, testis and ovary.[10]

Protein structure

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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.[3]

All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.[13] 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.[14][15]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.[14]Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.[14]

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.[3]Yet, ENaC is an obligate heterotrimer composed of three subunits as an αβγ or a βγδ trimer.[16]

Associated diseases

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So far mutations in the delta subunit have not been associated with a specific disease.[citation needed]

Notes

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References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000162572–Ensembl,May 2017
  2. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^abcdHanukoglu I, Hanukoglu A (January 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.PMC4756657.PMID26772908.
  4. ^Bourque CW (July 2008). "Central mechanisms of osmosensation and systemic osmoregulation".Nature Reviews. Neuroscience.9(7): 519–31.doi:10.1038/nrn2400.PMID18509340.S2CID205504313.
  5. ^Rossier BC, Baker ME, Studer RA (January 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.PMID25540145.
  6. ^Waldmann R, Champigny G, Bassilana F, Voilley N, Lazdunski M (November 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.PMID7499195.
  7. ^Yamamura H, Ugawa S, Ueda T, Nagao M, Shimada S (October 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.PMID16930535.
  8. ^Giraldez T, Afonso-Oramas D, Cruz-Muros I, Garcia-Marin V, Pagel P, González-Hernández T, Alvarez de la Rosa D (August 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.PMID17472699.S2CID18291486.
  9. ^Ji HL, Zhao RZ, Chen ZX, Shetty S, Idell S, Matalon S (December 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.PMC3532584.PMID22983350.
  10. ^abGiraldez T, Rojas P, Jou J, Flores C, Alvarez de la Rosa D (August 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.PMID22573384.
  11. ^abEnuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A (March 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.PMID22207244.S2CID15178940.
  12. ^Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC (December 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.doi:10.1083/jcb.127.6.1907.PMC2120291.PMID7806569.
  13. ^Canessa CM, Merillat AM, Rossier BC (December 1994). "Membrane topology of the epithelial sodium channel in intact cells".The American Journal of Physiology.267(6 Pt 1): C1682–90.doi:10.1152/ajpcell.1994.267.6.C1682.PMID7810611.
  14. ^abcJasti J, Furukawa H, Gonzales EB, Gouaux E (September 2007). "Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH".Nature.449(7160): 316–23.Bibcode:2007Natur.449..316J.doi:10.1038/nature06163.PMID17882215.
  15. ^Baconguis I, Bohlen CJ, Goehring A, Julius D, Gouaux E (February 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.PMC4190031.PMID24507937.
  16. ^Hanukoglu I (2017)."ASIC and ENaC type sodium channels: Conformational states and the structures of the ion selectivity filters".The FEBS Journal.284(4): 525–545.doi:10.1111/febs.13840.PMID27580245.S2CID24402104.

Further reading

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