SCNN1G explained

The SCNN1G gene encodes for the γ 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 SCNN1D.[1]

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 (SCNN1) 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".

History

The first cDNA encoding the gamma subunit of ENaC was cloned and sequenced by Canessa et al. from rat mRNA.[4] A year later, two independent groups reported the cDNA sequences of the beta- and gamma-subunits of the human ENaC.[5] [6] The complete coding sequence human γ subunit was reported by Saxena et al.[7]

Gene structure

While the human gene SCNN1A is located in chromosome 12p,[8] the human genes encoding SCNN1B and SCNN1G are located in juxtoposition in the short arm of chromosome 16 (16p12-p13).[6] The structures of the human and rat SCNN1G genes were first reported by Thomas et al.[9] [10] Later studies by Saxena et al. reported the complete coding sequence of the human SCNN1G gene establishing that it has 13 exons [7] The positions of introns are conserved in all three human ENaC genes, SCNN1A, SCNN1B and SCNN1G.[11] The positions of the introns are also highly conserved across vertebrates See: Ensembl GeneTree.

Tissue-specific expression

The three ENaC subunits encoded by 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] [12] the respiratory airway,[13] the female reproductive tract, colon, salivary and sweat glands.

ENaC is also expressed in the tongue, where it has been shown to be essential for the perception of salt taste.[12]

The expression of ENaC subunit genes is regulated mainly by the mineralocorticoid hormone aldosterone that is activated by the renin-angiotensin system.[14] [15]

Protein structure

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 γ subunit shares 34% identity with the β subunit and 27 and 23% identity with the α and δ subunits.

All four ENaC subunit sequences have two hydrophobic stretches that form two transmembrane segments named as TM1 and TM2.[1] [16] 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.[1]

The structure of ENaC has not been yet determined. Yet, the structure of a homologous protein ASIC1 has been resolved.[17] [18] 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.

Site-directed mutagenesis of the human γ subunit suggests that ENaC subunits have a structure similar to that of ASIC1.[19] The ion selectivity filter of ENaC has been modeled based on the ASIC1 structure.[20]

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.[1]

In the carboxy terminus of three ENaC subunits, (α, β and γ) there is a special conserved consensus sequence PPPXYXXL that is called the PY motif. This sequence is recognized by the so-called WW domains in a special E3 ubiquitin-protein ligase named Nedd4-2.[21] Nedd4-2 ligates ubiquitin to the C-terminus of the ENaC subunit which marks the protein for degradation.[21]

Associated diseases

At present, three major hereditary disorders are known to be associated with mutations in the SCNN1G gene. These are:1. Multisystem pseudohypoaldosteronism, 2. Liddle syndrome, and 3. Cystic fibrosis-like disease.[1]

Multi-system form of type I pseudohypoaldosteronism (PHA1B)

The disease most commonly associated with mutations in SCNN1B is the multi-system form of type I pseudohypoaldosteronism (PHA1B) that was first characterized by A. Hanukoglu as an autosomal recessive disease.[22] 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. 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.[23] 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.[24]

In the majority of the patients with multi-system PHA1B a homozygous mutation or two compound heterozygous mutations have been detected.[25] [26] [27]

Liddle syndrome

Liddle syndrome is generally caused by mutations in the PY motif or truncation of the C-terminus including loss of the PY motif in the β or γ ENaC subunits.[28] [29] [30] [31] [32] [33] Even though there is a PY motif also in the α subunit, so far Liddle disease has not observed in association with a mutation in the α subunit. Liddle syndrome is inherited as an autosomal dominant disease with a phenotype that includes early onset hypertension, metabolic alkalosis and low levels of plasma renin activity and mineralocorticoid hormone aldosterone. In the absence of a recognizable PY motif, ubiquitin-protein ligase Nedd4-2 cannot bind to the ENaC subunit and hence cannot attach a ubiquitin to it. Consequently, proteolysis of ENaC by proteasome is inhibited and ENaC accumulates in the membrane leading to enhanced activity of ENaC that causes hypertension.[34] [35] [36] [37]

Interactions

SCNN1G has been shown to interact with:

See also

Further reading

Notes and References

  1. Hanukoglu I, Hanukoglu A . Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases. . Gene . 579 . 2 . 95–132 . Jan 2016 . 26772908 . 10.1016/j.gene.2015.12.061 . 4756657.
  2. Bourque CW . Central mechanisms of osmosensation and systemic osmoregulation . Nature Reviews. Neuroscience . 9 . 7 . 519–31 . Jul 2008 . 18509340 . 10.1038/nrn2400 . 205504313 .
  3. Rossier BC, Baker ME, Studer RA . Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited . Physiological Reviews . 95 . 1 . 297–340 . Jan 2015 . 25540145 . 10.1152/physrev.00011.2014 .
  4. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC . Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.. Nature . 367 . 6462 . 463–7 . Feb 1994 . 8107805 . 10.1038/367463a0 . 1994Natur.367..463C. 769822.
  5. McDonald FJ, Price MP, Snyder PM, Welsh MJ . Cloning and expression of the beta- and gamma-subunits of the human epithelial sodium channel . American Journal of Physiology . 268 . 5 Pt 1 . C1157–63 . May 1995 . 7762608 . 10.1152/ajpcell.1995.268.5.C1157 .
  6. Voilley N, Bassilana F, Mignon C, Merscher S, Mattéi MG, Carle GF, Lazdunski M, Barbry P . Cloning, chromosomal localization, and physical linkage of the beta and gamma subunits (SCNN1B and SCNN1G) of the human epithelial amiloride-sensitive sodium channel . Genomics . 28 . 3 . 560–5 . Aug 1995 . 7490094 . 10.1006/geno.1995.1188 .
  7. Saxena A, Hanukoglu I, Saxena D, Thompson RJ, Gardiner RM, Hanukoglu A . Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel alpha-, beta-, and gamma-subunit genes . Journal of Clinical Endocrinology and Metabolism . 87 . 7 . 3344–50 . Jul 2002 . 12107247 . 10.1210/jcem.87.7.8674 . free .
  8. Ludwig M, Bolkenius U, Wickert L, Marynen P, Bidlingmaier F . Structural organisation of the gene encoding the alpha-subunit of the human amiloride-sensitive epithelial sodium channel . Human Genetics . 102 . 5 . 576–81 . May 1998 . 9654208 . 10.1007/s004390050743. 22547152 .
  9. Thomas CP, Doggett NA, Fisher R, Stokes JB . Genomic organization and the 5' flanking region of the gamma subunit of the human amiloride-sensitive epithelial sodium channel . Journal of Biological Chemistry . 271 . 42 . 26062–6 . Oct 1996 . 8824247 . 10.1074/jbc.271.42.26062. free .
  10. Thomas CP, Auerbach SD, Zhang C, Stokes JB . The structure of the rat amiloride-sensitive epithelial sodium channel gamma subunit gene and functional analysis of its promoter . Gene . 228 . 1–2 . 111–22 . Mar 1999 . 10072764 . 10.1016/s0378-1119(99)00016-5.
  11. Saxena A, Hanukoglu I, Strautnieks SS, Thompson RJ, Gardiner RM, Hanukoglu A . Gene structure of the human amiloride-sensitive epithelial sodium channel beta subunit . Biochemical and Biophysical Research Communications . 252 . 1 . 208–213 . Nov 1998 . 9813171 . 10.1006/bbrc.1998.9625.
  12. Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC . 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 . Dec 1994 . 7806569 . 2120291 . 10.1083/jcb.127.6.1907.
  13. Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A . 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 . Mar 2012 . 22207244 . 10.1007/s00418-011-0904-1 . 15178940 .
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  16. Canessa CM, Merillat AM, Rossier BC . Membrane topology of the epithelial sodium channel in intact cells . The American Journal of Physiology . 267 . 6 Pt 1 . C1682–90 . Dec 1994 . 7810611 . 10.1152/ajpcell.1994.267.6.C1682 .
  17. Jasti J, Furukawa H, Gonzales EB, Gouaux E . Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH . Nature . 449 . 7160 . 316–23 . Sep 2007 . 17882215 . 10.1038/nature06163 . 2007Natur.449..316J .
  18. Baconguis I, Bohlen CJ, Goehring A, Julius D, Gouaux E . 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 . Feb 2014 . 24507937 . 10.1016/j.cell.2014.01.011 . 4190031.
  19. Edelheit O, Ben-Shahar R, Dascal N, Hanukoglu A, Hanukoglu I . Conserved charged residues at the surface and interface of epithelial sodium channel (ENaC) subunits: roles in cell surface expression and Na+ self-inhibition response . FEBS Journal . 281 . 8 . 2097–2111 . Apr 2014 . 24571549 . 10.1111/febs.12765 . 5807500 . free .
  20. Hanukoglu I . ASIC and ENaC type sodium channels: Conformational states and the structures of the ion selectivity filters . FEBS Journal . 284 . 4 . 525–545 . 2017 . 27580245 . 10.1111/febs.13840 . 24402104 .
  21. Rotin D, Staub O. Role of the ubiquitin system in regulating ion transport . Pflügers Archiv: European Journal of Physiology . 461 . 1 . 1–21 . Jan 2011 . 20972579 . 10.1007/s00424-010-0893-2. 23272309 .
  22. Hanukoglu A . Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects . The Journal of Clinical Endocrinology and Metabolism . 73 . 5 . 936–44 . Nov 1991 . 1939532 . 10.1210/jcem-73-5-936 .
  23. Strautnieks SS, Thompson RJ, Hanukoglu A, Dillon MJ, Hanukoglu I, Kuhnle U, Seckl J, Gardiner RM, Chung E . Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping . Human Molecular Genetics . 5 . 2 . 293–9 . Feb 1996 . 8824886 . 10.1093/hmg/5.2.293.
  24. 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 . Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1 . Nature Genetics . 12 . 3 . 248–53 . Mar 1996 . 8589714 . 10.1038/ng0396-248 . 8185511 .
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