Regulation of the epithelial sodium channel by accessory proteins

Abstract

The epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium fluxes in epithelial cells. Modulation of sodium reabsorption through the distal nephron ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium-channel activity (Liddle's syndrome and pseudohypoaldosteronism type 1), associated with contrasting effects on blood pressure. The mineralocorticoid aldosterone is a well-established modulator of sodium-channel activity. Considerable insight has now been gained into the intracellular signalling pathways linking aldosterone-mediated changes in gene transcription with changes in ion transport. Activating pathways include aldosterone-induced proteins and especially the serum- and glucocorticoid-inducible kinase (SGK) and the small G-protein, K-Ras 2A. Targeting of the ENaC for endocytosis and degradation is now emerging as a major mechanism for the down-regulation of channel activity. Several proteins acting in concert are an intrinsic part of this process but Nedd4 (neural precursor cell expressed developmentally down-regulated 4) is of central importance. Other mechanisms known to interact with ENaC and affect sodium transport include channel-activating protease 1 (CAP-1), a membrane-anchored protein, and the cystic fibrosis transmembrane regulator. The implications of research on accessory factors controlling ENaC activity are wide-ranging. Understanding cellular mechanisms controlling ENaC activity may provide a more detailed insight not only of ion-channel abnormalities in cystic fibrosis but also of the link between abnormal renal sodium transport and essential hypertension.

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport

“…9 In humans there is a direct link between defective ENaC physiology and disease in Liddle syndrome (hypertension) and pseudohypoaldosteronism (hypotension). 5,[10][11][12][13][14][15][16] ENaC is regulated by several intrinsic and external factors, the details of which have been reviewed previously. 3,4,10,17,18 An essential ENaC regulator is the mineralocorticoid hormone aldosterone, which is central to Na + homeostasis.…”

Regulation Fe65 localization to the nucleus by SGK1 phosphorylation of its Ser566 residue

“…The identification and characterization of SGK1 substrates may provide clues to our understanding of how SGK1 contributes to cell survival and death (3,4,8,10,11,18). We demonstrated that Fe65 is a SGK1 substrate that contains the consensus motif RxRxxS/Tφ: where φ is a hydrophobic amino acid, which subsequently demonstrated that phosphorylation of Fe65 by SGK1 controls its subcellular localization (Figs.…”

“…Serum-and glucocorticoid-induced kinase 1 (SGK1) is a Ser/Thr protein kinase that is transcriptionally regulated by serum and/or glucocorticoids in mammary epithelial cells and by Rat-2 fibroblasts (3,4). SGK1 is also transcriptionally regulated by cortico-steroids in several types of cells (5,6).…”

Candidate gene variation in gilthead sea bream reveals complex spatiotemporal selection patterns between marine and lagoon habitats

“…In this case, genetic differentiation was observed among M samples and was mainly explained by the distinctiveness of the SL-M sample. This locus was associated with the ubiquitin ligase nedd4-2 (neural precursor cell-expressed, developmentally down-regulated protein 4-2) gene, a gene involved in regulation of the epithelial sodium channel in several organs, including kidney in mouse (Gormley et al 2003, Bens et al 2006. It may therefore be associated with osmoregulation in sea bream, but this function has never been investigated in fish.…”