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SCNN1G  -  sodium channel, non-voltage-gated 1, gamma...

Homo sapiens

 
 
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Disease relevance of SCNN1G

  • Liddle's syndrome of hypertension and pseudoaldosteronism has been shown to arise from mutations in SCNN1B and SCNN1G [1].
  • Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is an uncommon inherited disorder characterized by salt-wasting and end-organ unresponsiveness to mineralocorticoids [2].
  • Sixteen-month-old transgenic rescue mice that were kept under a regular salt diet that contains a small amount of sodium (0.3% Na(+)) displayed a compensated PHA-1 phenotype with normal body weight, normal kidney index, normal blood pressure, but 6.3-fold elevated plasma aldosterone levels compared with the age-matched control group [3].
  • Temporal Fourier analysis was applied to Kr-81m ventilation scintigraphy to determine the amplitude (AMP1) and phase (PHA1) of the first harmonic of a single composite respiratory cycle and to compare regional patterns in subjects with obstructive pulmonary disease (COPD) and nonobstructed subjects [4].
 

High impact information on SCNN1G

  • These two chromosomal regions harbour the genes encoding the three subunits of the human amiloride sensitive epithelial sodium channel (hENaC): SCNN1B and SCNN1G on 16p and SCNN1A on 12p [2].
  • A complete genome search using homozygosity mapping in eleven consanguineous families with PHA1 provided conclusive evidence of linkage with heterogeneity [2].
  • The gammaENaC (-/-) newborn exhibits a phenotype that resembles the clinical manifestations of human neonatal PHA1 [5].
  • Transcriptional ENaC induction by butyrate led to synthesis of gamma-ENaC subunits, but correct targeting of ENaC channels to the apical cell membrane was dependent on corticosteroid hormones [6].
  • RESULTS: Butyrate up-regulated beta- and gamma-ENaC mRNA expression in HT-29/B6 cells and induced transcription from beta- and gamma-ENaC promoter constructs [6].
 

Chemical compound and disease context of SCNN1G

 

Biological context of SCNN1G

  • In the SCNN1G gene, we identified three missense mutations, A578V (n=1), P603S (n=1), and L609F (n=1) in a heterozygous state in addition to two synonymous ones, Ile550 (n=1) and Leu649 (n= 91, heterozygous; n=2, homozygous) [8].
  • To study gene regulation, the promoters of beta- and gamma-ENaC were analyzed in reporter gene assays [9].
  • Promoter analysis revealed that down-regulation of beta- and gamma-ENaC gene expression was primarily induced by tumor necrosis factor alpha [9].
  • Furthermore, 2 base substitutions in exon 13 were present in all the Chinese subjects compared with the published European SCNN1G DNA sequence [10].
  • Although the effects of the A(-173) allele were recessive and although the AA genotype was found in just 0.7% of our study population, we observed that this variation of human SCNN1G had significant effects on blood pressure [11].
 

Anatomical context of SCNN1G

  • Individually substituting C terminus-truncated alpha-, beta-, or gamma-ENaC subunits for their wild-type counterparts reversed the S1A-induced inhibition of I(Na), and oocytes expressing ENaC comprised of three C terminus-truncated subunits showed no S1A inhibition of I(Na) [12].
  • The results showed that T lymphocytes express the ENaC gamma subunit mRNA, and B lymphocytes the ENaC beta subunit mRNA [13].
  • Confocal microscopy of Madin-Darby canine kidney cell monolayers stably transfected with wild type, rat isoforms of alpha-, beta-, and gamma-ENaC revealed co-localization of alpha-ENaC with the cortical F-actin cytoskeleton both at the apical membrane and within the subapical cytoplasm [14].
  • Immunoblotting showed increased protein expression of alpha-ENaC, the 70-kDa form of gamma-ENaC, and the Na-Cl cotransporter (NCC) in kidney cortex in aldosterone-treated rats, whereas spironolactone decreased alpha-ENaC and NCC compared with control rats treated with lithium alone [15].
  • At the level of the single channel, submicromolar concentrations of hNE increased activity of near-silent ENaC approximately 108-fold in patches from NIH-3T3 cells expressing rat alpha-, beta-, and gamma-ENaC subunits [16].
 

Associations of SCNN1G with chemical compounds

 

Physical interactions of SCNN1G

 

Regulatory relationships of SCNN1G

 

Other interactions of SCNN1G

  • Stable transfection of GR-alpha restored intestine-specific glucocorticoid upregulation of beta- and gamma-ENaC in HT-29/B6 cells, which was followed by intact targeting of ENaC channels to the apical cell membrane and dose-dependent induction of electrogenic sodium absorption [22].
  • Indirect immunofluorescence microscopy revealed that delta-ENaC is co-expressed with alpha-, beta-, and gamma-ENaC in H441 cells at the protein level [23].
  • Also, using antibodies raised against alpha-, beta-, or gamma-ENaC, we detected syntaxin 1A in immunoprecipitates from Madin-Darby canine kidney cells stably transfected with alphabetagamma-ENaC [21].
  • Finally, the whole kidney abundances of alpha-1 Na-K-ATPase, alpha- beta-, and gamma-ENaC (70-kDa band) positively correlated with net sodium balance, whereas NKCC2 was negatively correlated to FE(Na) [24].
  • Ribonuclease protection assays revealed that the steady-state levels of alpha-, beta-, and gamma-ENaC mRNAs were similar in CF and normal airway superficial epithelia [25].
 

Analytical, diagnostic and therapeutic context of SCNN1G

  • We now report the molecular cloning of the human lung beta (SCNN1B) and gamma (SCNN1G) chains [26].
  • Western blots showed that both alpha- and beta- but not gamma-ENaC proteins are expressed and strongly reduced by antisense oligonucleotides [17].
  • Although both transcription factors increased butyrate-mediated gamma-ENaC transcription upon overexpression, chromatin immunoprecipitation revealed that only Sp3 binds to the gamma-ENaC promoter in vivo and that Sp3 binding is enhanced by butyrate [6].
  • The bulk of whole cell gamma-ENaC was degraded within 1 h after treatment with inhibitors of synthesis; however, a significant pool was "protected" from inhibitors for up to 12 h [27].

References

  1. Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping. Strautnieks, S.S., Thompson, R.J., Hanukoglu, A., Dillon, M.J., Hanukoglu, I., Kuhnle, U., Seckl, J., Gardiner, R.M., Chung, E. Hum. Mol. Genet. (1996) [Pubmed]
  2. A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families. Strautnieks, S.S., Thompson, R.J., Gardiner, R.M., Chung, E. Nat. Genet. (1996) [Pubmed]
  3. Chronic hyperaldosteronism in a transgenic mouse model fails to induce cardiac remodeling and fibrosis under a normal-salt diet. Wang, Q., Clement, S., Gabbiani, G., Horisberger, J.D., Burnier, M., Rossier, B.C., Hummler, E. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  4. Regional distribution of ventilation assessed by Kr-81m scintigraphy employing temporal Fourier transform. Slosman, D., Susskind, H., Cinotti, L., van Giessen, J.W., Brill, A.B. American journal of physiologic imaging. (1986) [Pubmed]
  5. Role of gammaENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism. Barker, P.M., Nguyen, M.S., Gatzy, J.T., Grubb, B., Norman, H., Hummler, E., Rossier, B., Boucher, R.C., Koller, B. J. Clin. Invest. (1998) [Pubmed]
  6. Butyrate induces intestinal sodium absorption via Sp3-mediated transcriptional up-regulation of epithelial sodium channels. Zeissig, S., Fromm, A., Mankertz, J., Weiske, J., Zeitz, M., Fromm, M., Schulzke, J.D. Gastroenterology (2007) [Pubmed]
  7. New insights into the pathogenesis of renal tubular acidosis--from functional to molecular studies. Rodríguez-Soriano, J. Pediatr. Nephrol. (2000) [Pubmed]
  8. Six missense mutations of the epithelial sodium channel beta and gamma subunits in Japanese hypertensives. Kamide, K., Tanaka, C., Takiuchi, S., Miwa, Y., Yoshii, M., Horio, T., Kawano, Y., Miyata, T. Hypertens. Res. (2004) [Pubmed]
  9. Cytokine-dependent transcriptional down-regulation of epithelial sodium channel in ulcerative colitis. Amasheh, S., Barmeyer, C., Koch, C.S., Tavalali, S., Mankertz, J., Epple, H.J., Gehring, M.M., Florian, P., Kroesen, A.J., Zeitz, M., Fromm, M., Schulzke, J.D. Gastroenterology (2004) [Pubmed]
  10. Identification of a novel intron and 4 polymorphisms in the gene encoding the gamma subunit of the epithelial sodium channel. Xu, X., Niu, T., Chen, C., Yang, J., Fang, Z., Xu, X. Hum. Biol. (1999) [Pubmed]
  11. Association of sodium channel gamma-subunit promoter variant with blood pressure. Iwai, N., Baba, S., Mannami, T., Katsuya, T., Higaki, J., Ogihara, T., Ogata, J. Hypertension (2001) [Pubmed]
  12. Syntaxin 1A regulates ENaC via domain-specific interactions. Condliffe, S.B., Carattino, M.D., Frizzell, R.A., Zhang, H. J. Biol. Chem. (2003) [Pubmed]
  13. Amiloride-sensitive epithelial sodium channel subunits are expressed in human and mussel immunocytes. Ottaviani, E., Franchini, A., Mandrioli, M., Saxena, A., Hanukoglu, A., Hanukoglu, I. Dev. Comp. Immunol. (2002) [Pubmed]
  14. The carboxyl terminus of the alpha-subunit of the amiloride-sensitive epithelial sodium channel binds to F-actin. Mazzochi, C., Bubien, J.K., Smith, P.R., Benos, D.J. J. Biol. Chem. (2006) [Pubmed]
  15. Lithium-induced NDI in rats is associated with loss of alpha-ENaC regulation by aldosterone in CCD. Nielsen, J., Kwon, T.H., Frøkiaer, J., Knepper, M.A., Nielsen, S. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  16. Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport. Caldwell, R.A., Boucher, R.C., Stutts, M.J. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  17. Steroids and exogenous gamma-ENaC subunit modulate cation channels formed by alpha-ENaC in human B lymphocytes. Ma, H.P., Al-Khalili, O., Ramosevac, S., Saxena, S., Liang, Y.Y., Warnock, D.G., Eaton, D.C. J. Biol. Chem. (2004) [Pubmed]
  18. Dual therapeutic utility of proteasome modulating agents for pharmaco-gene therapy of the cystic fibrosis airway. Zhang, L.N., Karp, P., Gerard, C.J., Pastor, E., Laux, D., Munson, K., Yan, Z., Liu, X., Godwin, S., Thomas, C.P., Zabner, J., Shi, H., Caldwell, C.W., Peluso, R., Carter, B., Engelhardt, J.F. Mol. Ther. (2004) [Pubmed]
  19. Glucocorticoid regulation of genes in the amiloride-sensitive sodium transport pathway by semicircular canal duct epithelium of neonatal rat. Pondugula, S.R., Raveendran, N.N., Ergonul, Z., Deng, Y., Chen, J., Sanneman, J.D., Palmer, L.G., Marcus, D.C. Physiol. Genomics (2006) [Pubmed]
  20. Identification of new partners of the epithelial sodium channel alpha subunit. Malbert-Colas, L., Nicolas, G., Galand, C., Lecomte, M.C., Dhermy, D. C. R. Biol. (2003) [Pubmed]
  21. ENaC subunit-subunit interactions and inhibition by syntaxin 1A. Berdiev, B.K., Jovov, B., Tucker, W.C., Naren, A.P., Fuller, C.M., Chapman, E.R., Benos, D.J. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  22. Restoration of ENaC expression by glucocorticoid receptor transfection in human HT-29/B6 colon cells. Zeissig, S., Fromm, A., Mankertz, J., Zeitz, M., Fromm, M., Schulzke, J.D. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  23. Delta-subunit confers novel biophysical features to alpha beta gamma-human epithelial sodium channel (ENaC) via a physical interaction. Ji, H.L., Su, X.F., Kedar, S., Li, J., Barbry, P., Smith, P.R., Matalon, S., Benos, D.J. J. Biol. Chem. (2006) [Pubmed]
  24. Rosiglitazone regulates ENaC and Na-K-2Cl cotransporter (NKCC2) abundance in the obese Zucker rat. Riazi, S., Khan, O., Tiwari, S., Hu, X., Ecelbarger, C.A. American journal of nephrology. (2006) [Pubmed]
  25. Relative expression of the human epithelial Na+ channel subunits in normal and cystic fibrosis airways. Burch, L.H., Talbot, C.R., Knowles, M.R., Canessa, C.M., Rossier, B.C., Boucher, R.C. Am. J. Physiol. (1995) [Pubmed]
  26. Cloning, chromosomal localization, and physical linkage of the beta and gamma subunits (SCNN1B and SCNN1G) of the human epithelial amiloride-sensitive sodium channel. Voilley, N., Bassilana, F., Mignon, C., Merscher, S., Mattéi, M.G., Carle, G.F., Lazdunski, M., Barbry, P. Genomics (1995) [Pubmed]
  27. Targeted degradation of ENaC in response to PKC activation of the ERK1/2 cascade. Booth, R.E., Stockand, J.D. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
 
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