SCNN1A

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SCNN1A
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SCNN1A, BESC2, ENaCa, ENaCalpha, SCNEA, SCNN1, sodium channel epithelial 1 alpha subunit
External IDs MGI: 101782 HomoloGene: 811 GeneCards: SCNN1A
Gene location (Human)
Chromosome 12 (human)
Chr. Chromosome 12 (human)[1]
Chromosome 12 (human)
Genomic location for SCNN1A
Genomic location for SCNN1A
Band No data available Start 6,346,843 bp[1]
End 6,377,730 bp[1]
RNA expression pattern
PBB GE SCNN1A 215026 x at fs.png

PBB GE SCNN1A 203453 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001159576
NM_001038
NM_001159575

NM_011324

RefSeq (protein)

NP_001029
NP_001153047
NP_001153048

NP_035454

Location (UCSC) Chr 12: 6.35 – 6.38 Mb Chr 12: 125.32 – 125.34 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The SCNN1A gene encodes for the α 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.[5] The other ENAC subunits are encoded by SCNN1B, SCNN1G, and SCNN1D.

ENaC is expressed in epithelial cells[5] 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 (SCNN1A) represents that these are NON-voltage-gated channels.

In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.[6] 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.[7]

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

History[edit]

The first mRNA encoding the alpha subunit of ENaC was isolated by two independent groups by screening a rat colon cDNA library.[8][9]

Gene structure[edit]

The human gene SCNN1A is located in the short arm of chromosome 12 (12p3).[10] [11] Human SCNN1A includes 13 exons spanning about 29,000 bp. The protein coding region is located in exons 2-13.[11] The positions of introns are conserved in all four human ENaC genes.[12] The positions of the introns are also highly conserved across vertebrates See: Ensembl GeneTree.

Analysis of α subunit mRNA from human lung and kidney showed that during transcription of SCNN1A gene different mRNAs are produced as a result of alternative translation initiation and splicing sites. The isoforms translated from these differ in their activities.[13][14][15][16]

Fig. 1. Exon-intron structures of three transcripts of SCNN1A. 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.

Tissue-specific expression[edit]

SCNN1A, SCNN1B, and SCNN1G are commonly expressed in tight epithelia that have low water permeability. The major organs where ENaC is expressed include parts of the kidney tubular epithelia,[5][7][17] the respiratory airway,[18] the female reproductive tract,[18] colon, salivary and sweat glands.[17] In the skin, SCNN1A is expressed in the keratinocytes in the epidermal layer, in the sebaceous sweat glands, and the smooth muscle cells mostly within the cytoplasm.[19] In contrast, in the eccrine sweat glands ENaC is mostly located on the luminal surface of eccrine duct epithelia.[19]

ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.[17]

The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.[20][21] [22]

Protein structure[edit]

The primary structures of all four ENaC subunits show strong similarity.[5] 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 α subunit shares 34% identity with the δ subunit and 26-27% 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.[23] 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.[24][25] 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.[24] Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.[24]

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.[26][27][28]

Associated diseases[edit]

The disease most commonly associated with mutations in SCNN1A is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease.[29] This is a syndrome of unresponsiveness to aldosterone in patients that have high serum levels of aldosterone but suffer from symptoms of aldosterone deficiency with a high risk of mortality due to severe salt loss.[5] Initially, this disease was thought to be a result of a mutation in the mineralocorticoid receptor (NR3C2) that binds aldosterone. But homozygosity mapping in 11 affected families revealed that the disease is associated with two loci on chromosome 12p13.1-pter and chromosome 16p12.2-13 that include the genes for SCNN1A and SCNN1B and SCNN1G respectively.[30] Sequencing of the ENaC genes identified mutation in affected patients, and functional expression of the mutated cDNAs further confirmed that identified mutations lead to the loss of activity of ENaC.[31]

In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.[32][33][34]

Interactions[edit]

SCNN1A has been shown to interact with:

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000111319 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030340 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ a b c d e Hanukoglu I, Hanukoglu A (April 2016). "Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases". Gene. 579 (2): 95–132. PMC 4756657Freely accessible. PMID 26772908. doi:10.1016/j.gene.2015.12.061. 
  6. ^ Bourque CW (July 2008). "Central mechanisms of osmosensation and systemic osmoregulation". Nature Reviews. Neuroscience. 9 (7): 519–31. PMID 18509340. doi:10.1038/nrn2400. 
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  8. ^ Lingueglia E, Voilley N, Waldmann R, Lazdunski M, Barbry P (February 1993). "Expression cloning of an epithelial amiloride-sensitive Na+ channel. A new channel type with homologies to Caenorhabditis elegans degenerins". FEBS Letters. 318 (1): 95–9. PMID 8382172. doi:10.1016/0014-5793(93)81336-x. 
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  11. ^ a b Ludwig M, Bolkenius U, Wickert L, Marynen P, Bidlingmaier F (May 1998). "Structural organisation of the gene encoding the alpha-subunit of the human amiloride-sensitive epithelial sodium channel". Human Genetics. 102 (5): 576–81. PMID 9654208. doi:10.1007/s004390050743. 
  12. ^ Saxena A, Hanukoglu I, Strautnieks SS, Thompson RJ, Gardiner RM, Hanukoglu A (November 1998). "Gene structure of the human amiloride-sensitive epithelial sodium channel beta subunit". Biochemical and Biophysical Research Communications. 252 (1): 208–13. PMID 9813171. doi:10.1006/bbrc.1998.9625. 
  13. ^ Thomas CP, Auerbach S, Stokes JB, Volk KA (May 1998). "5' heterogeneity in epithelial sodium channel alpha-subunit mRNA leads to distinct NH2-terminal variant proteins". The American Journal of Physiology. 274 (5 Pt 1): C1312–23. PMID 9612219. 
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  19. ^ a b Hanukoglu I, Boggula VR, Vaknine H, Sharma S, Kleyman T, Hanukoglu A (January 2017). "Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages". Histochemistry and Cell Biology. 147 (6): 733–748. PMID 28130590. doi:10.1007/s00418-016-1535-3. 
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  25. ^ 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. PMC 4190031Freely accessible. PMID 24507937. doi:10.1016/j.cell.2014.01.011. 
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  27. ^ Edelheit O, Ben-Shahar R, Dascal N, Hanukoglu A, Hanukoglu I (April 2014). "Conserved charged residues at the surface and interface of epithelial sodium channel subunits--roles in cell surface expression and the sodium self-inhibition response". The FEBS Journal. 281 (8): 2097–111. PMID 24571549. doi:10.1111/febs.12765. 
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  31. ^ Chang SS, Grunder S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, Lifton RP (March 1996). "Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1". Nature Genetics. 12 (3): 248–53. PMID 8589714. doi:10.1038/ng0396-248. 
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  40. ^ Raikwar NS, Thomas CP (May 2008). "Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel". American Journal of Physiology. Renal Physiology. 294 (5): F1157–65. PMC 2424110Freely accessible. PMID 18322022. doi:10.1152/ajprenal.00339.2007. 

Further reading[edit]

External links[edit]