From Wikipedia, the free encyclopedia
Jump to: navigation, search
Available structures
PDB Ortholog search: PDBe RCSB
Aliases SCNN1A, BESC2, ENaCa, ENaCalpha, SCNEA, SCNN1, sodium channel epithelial 1 alpha subunit
External IDs MGI: 101782 HomoloGene: 811 GeneCards: 6337
Genetically Related Diseases
Disease Name References
morbid obesity
RNA expression pattern
PBB GE SCNN1A 203453 at tn.png

PBB GE SCNN1A 215026 x at tn.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 12: 6.35 – 6.38 Mb Chr 6: 125.32 – 125.34 Mb
PubMed search [2] [3]
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.[1] The other ENAC subunits are encoded by SCNN1B, SCNN1G, and SCNN1D.

ENaC is expressed in epithelial cells[1] 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.[2] 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.[3]

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


The first mRNA encoding the alpha subunit of ENaC was isolated by two independent groups by screening a rat colon cDNA library.[4][5]

Gene structure[edit]

The human gene SCNN1A is located in the short arm of chromosome 12 (12p3).[6] [7] Human SCNN1A includes 13 exons spanning about 29,000 bp. The protein coding region is located in exons 2-13.[7] The positions of introns are conserved in all four human ENaC genes.[8] 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.[9][10][11][12]

Alt text
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,[1][3][13] the respiratory airway,[14] the female reproductive tract,[14] colon, salivary and sweat glands.[13]

ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.[13]

The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.[15][16] [17]

Protein structure[edit]

The primary structures of all four ENaC subunits show strong similarity.[1] 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.[18] 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.[19][20] 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.[19] Hence distinct domains of ASIC1 have been referred to as palm, knuckle, finger, thumb, and β-ball.[19]

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.

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.[21] 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.[1] 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.[22] 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.[23]

In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.[24][25][26]


SCNN1A has been shown to interact with:

See also[edit]


  1. ^ a b c d e 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. 
  2. ^ Bourque CW (Jul 2008). "Central mechanisms of osmosensation and systemic osmoregulation". Nature Reviews. Neuroscience 9 (7): 519–31. doi:10.1038/nrn2400. PMID 18509340. 
  3. ^ a b 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. 
  4. ^ Lingueglia E, Voilley N, Waldmann R, Lazdunski M, Barbry P (Feb 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. 
  5. ^ Canessa CM, Horisberger JD, Rossier BC (Feb 1993). "Epithelial sodium channel related to proteins involved in neurodegeneration". Nature 361 (6411): 467–70. doi:10.1038/361467a0. PMID 8381523. 
  6. ^ Meisler MH, Barrow LL, Canessa CM, Rossier BC (Nov 1994). "SCNN1, an epithelial cell sodium channel gene in the conserved linkage group on mouse chromosome 6 and human chromosome 12". Genomics 24 (1): 185–6. doi:10.1006/geno.1994.1599. PMID 7896277. 
  7. ^ 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. 
  8. ^ Saxena A, Hanukoglu I, Strautnieks SS, Thompson RJ, Gardiner RM, Hanukoglu A (Nov 1998). "Gene structure of the human amiloride-sensitive epithelial sodium channel beta subunit". Biochemical and Biophysical Research Communications 252 (1): 208–13. doi:10.1006/bbrc.1998.9625. PMID 9813171. 
  9. ^ 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. 
  10. ^ Chow YH, Wang Y, Plumb J, O'Brodovich H, Hu J (Aug 1999). "Hormonal regulation and genomic organization of the human amiloride-sensitive epithelial sodium channel alpha subunit gene". Pediatric Research 46 (2): 208–14. PMID 10447117. 
  11. ^ Tucker JK, Tamba K, Lee YJ, Shen LL, Warnock DG, Oh Y (Apr 1998). "Cloning and functional studies of splice variants of the alpha-subunit of the amiloride-sensitive Na+ channel". The American Journal of Physiology 274 (4 Pt 1): C1081–9. PMID 9575806. 
  12. ^ Berman JM, Brand C, Awayda MS (2015). "A long isoform of the epithelial sodium channel alpha subunit forms a highly active channel". Channels 9 (1): 30–43. doi:10.4161/19336950.2014.985478. PMID 25517724. 
  13. ^ a b c 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". Journal of Cell Biology 127 (6 Pt 2): 1907–21. PMID 7806569. 
  14. ^ a b 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. 
  15. ^ Mick VE, Itani OA, Loftus RW, Husted RF, Schmidt TJ, Thomas CP (Apr 2001). "The alpha-subunit of the epithelial sodium channel is an aldosterone-induced transcript in mammalian collecting ducts, and this transcriptional response is mediated via distinct cis-elements in the 5'-flanking region of the gene". Molecular Endocrinology 15 (4): 575–88. doi:10.1210/me.15.4.575. PMID 11266509. 
  16. ^ Palmer LG, Patel A, Frindt G (Feb 2012). "Regulation and dysregulation of epithelial Na+ channels". Clinical and Experimental Nephrology 16 (1): 35–43. doi:10.1007/s10157-011-0496-z. PMID 22038262. 
  17. ^ Thomas W, Harvey BJ (2011). "Mechanisms underlying rapid aldosterone effects in the kidney". Annual Review of Physiology 73: 335–57. doi:10.1146/annurev-physiol-012110-142222. PMID 20809792. 
  18. ^ 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. 
  19. ^ a b c 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. 
  20. ^ 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. 
  21. ^ Hanukoglu A (Nov 1991). "Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects". Journal of Clinical Endocrinology and Metabolism 73 (5): 936–44. doi:10.1210/jcem-73-5-936. PMID 1939532. 
  22. ^ Strautnieks SS, Thompson RJ, Hanukoglu A, Dillon MJ, Hanukoglu I, Kuhnle U, Seckl J, Gardiner RM, Chung E (Feb 1996). "Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping". Human Molecular Genetics 5 (2): 293–9. PMID 8824886. 
  23. ^ 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 (Mar 1996). "Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1". Nature Genetics 12 (3): 248–53. doi:10.1038/ng0396-248. PMID 8589714. 
  24. ^ Strautnieks SS, Thompson RJ, Gardiner RM, Chung E (Jun 1996). "A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families". Nature Genetics 13 (2): 248–50. doi:10.1038/ng0696-248. PMID 8640238. 
  25. ^ Edelheit O, Hanukoglu I, Gizewska M, Kandemir N, Tenenbaum-Rakover Y, Yurdakök M, Zajaczek S, Hanukoglu A (May 2005). "Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism". Clinical Endocrinology 62 (5): 547–53. doi:10.1111/j.1365-2265.2005.02255.x. PMID 15853823. 
  26. ^ Zennaro MC, Hubert EL, Fernandes-Rosa FL (Mar 2012). "Aldosterone resistance: structural and functional considerations and new perspectives". Molecular and Cellular Endocrinology 350 (2): 206–15. doi:10.1016/j.mce.2011.04.023. PMID 21664233. 
  27. ^ a b Harvey KF, Dinudom A, Cook DI, Kumar S (Mar 2001). "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel". Journal of Biological Chemistry 276 (11): 8597–601. doi:10.1074/jbc.C000906200. PMID 11244092. 
  28. ^ Malbert-Colas L, Nicolas G, Galand C, Lecomte MC, Dhermy D (Jul 2003). "Identification of new partners of the epithelial sodium channel alpha subunit". Comptes Rendus Biologies 326 (7): 615–24. doi:10.1016/s1631-0691(03)00154-9. PMID 14556380. 
  29. ^ Farr TJ, Coddington-Lawson SJ, Snyder PM, McDonald FJ (Feb 2000). "Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits". The Biochemical Journal. 345 Pt 3: 503–9. doi:10.1042/0264-6021:3450503. PMC 1220784. PMID 10642508. 
  30. ^ McDonald FJ, Western AH, McNeil JD, Thomas BC, Olson DR, Snyder PM (Sep 2002). "Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel". American Journal of Physiology. Renal Physiology 283 (3): F431–6. doi:10.1152/ajprenal.00080.2002. PMID 12167593. 
  31. ^ Boulkroun S, Ruffieux-Daidié D, Vitagliano JJ, Poirot O, Charles RP, Lagnaz D, Firsov D, Kellenberger S, Staub O (Oct 2008). "Vasopressin-inducible ubiquitin-specific protease 10 increases ENaC cell surface expression by deubiquitylating and stabilizing sorting nexin 3". American Journal of Physiology. Renal Physiology 295 (4): F889–900. doi:10.1152/ajprenal.00001.2008. PMID 18632802. 
  32. ^ 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. doi:10.1152/ajprenal.00339.2007. PMC 2424110. PMID 18322022. 

Further reading[edit]

External links[edit]