Disease relevance of Scnn1a

• Selected contribution: limiting Na(+) transport rate in airway epithelia from alpha-ENaC transgenic mice: a model for pulmonary edema [1].
• An experimental animal model with a reduced expression of ENaC, the alpha-ENaC transgenic rescue mouse, is prone to develop edema under hypoxia exposure [1].
• The importance of epithelial sodium channel (ENaC) in this clearance has been demonstrated in animal studies in which alpha-ENaC knockout mice died postnatally as a result of respiratory insufficiency [2].

High impact information on Scnn1a

• Short interfering RNA-induced knockdown of 14-3-3beta blunted the aldosterone-induced increase in alpha-ENaC expression, returned alpha-ENaC-Nedd4-2 binding toward prealdosterone levels, and blocked the aldosterone-stimulated increase in transepithelial sodium transport [3].
• Immunostaining indicated localization of ENaC-alpha to the flagellar midpiece and of ENaC-delta to the acrosome [4].
• Indeed, ENaC-alpha and -delta mRNAs were detected by reverse transcription-PCR in extracts of isolated elongated spermatids, and ENaC-alpha and -delta proteins were found on immunoblots of sperm membrane preparations [4].
• Alanine substitution of the conserved Thr within the YXX motif of gamma-mENaC (T635A) increased basal activity [5].
• Using the Xenopus oocyte expression system, differences in functional regulatory interactions were observed when CFTR was co-expressed with either alphabetagamma mENaC or alphabetagamma human ENaC (hENaC) [6].

Biological context of Scnn1a

• Using transient transfections of serial deletion mutants into Scnn1a-expressing cells, we demonstrate that 1.56 kb of 5' upstream sequence is required for cell-specific expression and corticosteroid-mediated regulation [7].
• These 5' sequences are not sufficient to drive expression of a lacZ reporter gene or a rat Scnn1a cDNA in transgenic mice, where they failed to rescue Scnn1a deficiency [7].
• Assessment of regulatory interactions between CFTR and chimeric mouse/human ENaCs suggest that the 20 C-terminal amino acid residues of alpha ENaC confer species specificity regarding ENaC inhibition by activated CFTR [6].
• Specific immune sera to ENaC subunits showed up-regulation of alpha-ENaC in synaptic and nuclear layers of the retina, and in the retinal pigment epithelium [8].
• Finally, the increase of alpha-ENaC gene expression in the neuronal retina and the retinal pigment epithelium was not observed in other tissues of DBA/2J mice [8].

Anatomical context of Scnn1a

• Modulation of alpha-ENaC and alpha1-Na+-K+-ATPase by cAMP and dexamethasone in alveolar epithelial cells [9].
• Intense expression of mENaC subunits in medium and small airway epithelium and in ATII cells suggests that these regions are a primary location for liquid absorption in the perinatal and postnatal murine lung [10].
• In animals, the expression of alpha-ENaC in respiratory epithelium is dependent on gestational age, but when assessed by in situ hybridization in the human (h), the mRNA is present from the earliest stages of pulmonary development [2].

Associations of Scnn1a with chemical compounds

• In contrast, alpha-ENaC was markedly upregulated, and the molecular weight of a large fraction of gamma-ENaC subunits was shifted from 85 to 70 kD, consistent with previous results from rat models with elevated plasma aldosterone levels [11].
• Similarly, mutation of the proline repeat in the PY motif of gamma-mENaC disrupted only Nedd4-2 regulation having no effect on regulation by K44A and epsin [5].
• Compensatory up-regulation of angiotensin II subtype 1 receptors in alpha ENaC knockout heterozygous mice [12].
• DBcAMP and dexamethasone modulated transepithelial current with a time course reminiscent of the profile observed for alpha-ENaC mRNA expression [9].
• Cysteine substitution at the site equivalent to alphaAsp(602) within beta mENaC (betaD544C) did not alter either Li(+)/Na(+) or K(+)/Na(+) current ratios, although mutation of the equivalent site within gamma mENaC (gammaD562C) significantly increased the Li(+)/Na(+) current ratio [13].
• Acute stimulation of the recycling pool of ENaC was unaffected by apical cyclodextrin application [14].

Regulatory relationships of Scnn1a

• Dexamethasone augmented alpha-ENaC mRNA expression 4.4-fold in cells treated for 24 h and also upregulated beta- and gamma-ENaC mRNA [9].

Other interactions of Scnn1a

• In mice, this channel is composed of three subunits (alpha, beta, and gamma), which are encoded by different genes (Scnn1a, Scnn1b, and Scnn1c, respectively) [15].
• Channels containing the T635(D/E) substitution in gamma-mENaC did not have increased basal activity and responded to Nedd4-2 but not K44A [5].
• The observed order of mouse genes was centromere-Raf1-(2.1 +/- 2.1)-Scnn1, Vwf-(1.9 +/- 1.9)-Ntf3, with 0/101 recombinants between Scnn1 and Vwf [16].
• KGF-induced fluid accumulation is driven by CFTR-independent Cl- transport and associated with decreased expression of alpha-ENaC [17].
• Plasma aldosterone concentration was higher in Gal 3-/- than in WT mice (p < 0.04), which probably caused the observed increase in alpha-epithelial sodium channel (alpha-ENaC) protein abundance in the mutant mice (p < 0.001) [18].

Analytical, diagnostic and therapeutic context of Scnn1a

• Conditional gene targeting of the Scnn1a (alphaENaC) gene locus [19].
• Using reverse transcriptase polymerase chain reaction we observed a significant increase of alpha-ENaC in the neuronal retina of DBA/2J mice when compared with control animals, while beta-ENaC and gamma-ENaC were not detectable in this tissue [8].
• Two-electrode voltage-clamp and ion-selective microelectrodes were used to measure the Na(+) current, intracellular pH (pH(i)), and ion activities in oocytes expressing mENaC [20].

References