Disease relevance of Scnn1a

• Increased renal alpha-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape [1].
• On Western blots of ATII cell membranes, alpha-ENaC subunit protein slightly increased, whereas the amount of alpha(1)- and beta(1)-Na,K-ATPase protein were unchanged with hypoxia [2].

High impact information on Scnn1a

• We have demonstrated that both the UMR-106 osteoblast-like cell line and human osteoblasts in primary culture express the alpha-subunit of the epithelial sodium channel (alpha-ENaC) [3].
• This reduction in ion and water transport across the lung epithelium is in large part due to a decrease in alpha ENaC expression through p38 MAPK-dependent inhibition of alpha ENaC promoter activity and to an alteration in ENaC trafficking to the apical membrane of ATII cells [4].
• The ENaC is a multimeric protein composed of alpha-ENaC, beta-ENaC, and gamma-ENaC subunits [5].
• Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) transcription by Ras activation in salivary epithelial cells [6].
• Together, our results demonstrate that Ras/ERK-mediated induction of HMGI-C is required to effectively repress GR/Dex-stimulated transcription of alpha-ENaC gene and STAT3-mediated transactivation [6].

Biological context of Scnn1a

• Distal lung explants from late gestation wild-type and alpha-ENaC-deficient fetal mice, which normally expand due to liquid secretion, decreased in size due to liquid absorption when exposed to EF [7].
• These data indicate that, in MHS rats, there is a strong upregulation of NKCC2 along the TAL associated with increased GFR, robust inhibition of NCC cotransporter along the DCT and modest downregulation of alpha-ENaC along the CD [8].
• Although ENaC activity is strictly dependent upon its alpha-subunit expression, little is known about the molecular mechanisms by which cells modulate alpha-ENaC gene expression [9].
• The amino acid sequence of the rabbit alpha-ENaC cloned from native rabbit esophageal epithelia was not significantly different from that of other published alpha-ENaC homologs [10].
• We conclude that alpha-ENaC mRNA and functional Na+ channel protein are expressed already before morphogenesis of the CCD is completed and prior to the onset of epithelial NaCl reabsorption [11].

Anatomical context of Scnn1a

• Immunoelectron microscopy further revealed an increased labeling of alpha-ENaC in the apical plasma membrane of cortical collecting duct principal cells of PAN-treated rats, indicating enhanced apical targeting of alpha-ENaC subunits [12].
• The alpha-ENaC-positive tissues were also positive for beta-subunit mRNA (except spiral ganglion) or for gamma-subunit mRNA (spiral limbus, spiral ligament, and spiral ganglion), but the signals of beta- and gamma-subunits were weaker than those observed for alpha-subunit [13].
• In summary, this study presents a mechanism by which alpha-ENaC expression is regulated in salivary epithelial cells [9].
• Unlike alpha ENAC, expression of alpha ENACa in Xenopus oocytes fails to generate amiloride-sensitive Na+ or Li+ currents [14].
• Based upon our previous study showing expression of alpha-ENaC and functional amiloride-sensitive currents in rabbit Muller cells, we expected changes in Muller cell components of the ERG [15].

Associations of Scnn1a with chemical compounds

• Sucrose density gradient distributions were comparable for the endogenously expressed alpha-ENaC 5'UTRs in rat lung at Fetal Day 20 or Postnatal Day 1 using Northern analysis [16].
• In conclusion, the rapid in vivo accumulation of SGK and alpha-ENaC after aldosterone injection takes place along the entire ASDN, whereas the translocation of alpha,beta,gamma-ENaC to the apical plasma membrane is restricted to its proximal portions [17].
• Analysis of immunoblots revealed marked increases in the abundances of both of the major aldosterone-sensitive apical transport proteins of the renal tubule, namely the thiazide-sensitive NaCl cotransporter NCC and the epithelial sodium channel alpha subunit (alpha-ENaC) [18].
• Type 3 sodium/hydrogen exchanger (NHE3), bumetanide-sensitive sodium-potassium-2 chloride cotransporter (NKCC2), sodium-chloride cotransporter (NCC) and alpha-ENaC mRNA abundances were quantified by competitive PCR [8].
• Five-day infusion of dDAVP (a V(2) receptor agonist) to Brattleboro rats lacking vasopressin induced a marked increase in beta- and gamma-subunit ENaC mRNA levels in the renal cortex (beta, 85%; gamma, 100%), with no change in alpha-ENaC mRNA [19].

Other interactions of Scnn1a

• Immunoperoxidase brightfield- and laser-scanning confocal fluorescence microscopy demonstrated increased targeting of alpha-ENaC, beta-ENaC, and gamma-ENaC subunits to the apical plasma membrane in the distal convoluted tubule (DCT2), connecting tubule, and cortical and medullary collecting duct segments [12].
• A strong correlation was found at different TNF-alpha concentrations between the decrease of amiloride-sensitive current and alpha-ENaC mRNA expression [20].
• Pretreatment of cells with a specific inhibitor of the ERK kinase pathway, PD 98059, markedly abolished the down-regulation of alpha-ENaC expression, consistent with the hypothesis that the ERK kinase-signaling pathway is involved in TPA-mediated repression [21].
• This report demon- strates for the first time that the cross-talk between glucocorticoid receptor and Ras/extracellular signal-regulated protein kinase signaling pathways results in an antagonistic effect at the transcriptional level to modulate alpha-ENaC expression through the identified GRE [9].
• The abundance of alpha-ENaC mRNA, when normalized by reference to beta-actin, was higher by a factor of 2 in postnatal (P1-6) UB and by a factor of 5 in CCD cells (P7-14) compared with the embryonic stage [11].

Analytical, diagnostic and therapeutic context of Scnn1a

• In cortex and outer medulla, confocal microscopy demonstrated a difference in the subcellular localization of subunits. alpha-ENaC was localized mainly in a zone in the apical domains, whereas beta- and gamma-ENaC were found throughout the cytoplasm [22].
• Here we show by real-time RT-PCR and immunofluorescence that an aldosterone injection in adrenalectomized rats induces alpha-ENaC subunit expression along the entire ASDN within 2 h, whereas beta- and gamma-ENaC are constitutively expressed [17].
• Semiquantitative immunoblotting demonstrated that the protein abundance of beta- and gamma-subunits of ENaC was increased in the cortex and outer stripe of the outer medulla and inner stripe of the outer medulla (ISOM) in SHR, whereas alpha-ENaC abundance was increased in ISOM [23].
• In this study we show that the putative pore forming subunit of the rat epithelial (amiloride-sensitive) Na+ channel (alpha ENaC) binds to alpha-spectrin in vivo, as determined by co-immunoprecipitation [24].

References