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      Regulation of Epithelial Sodium Transport via Epithelial Na + Channel

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          Abstract

          Renal epithelial Na + transport plays an important role in homeostasis of our body fluid content and blood pressure. Further, the Na + transport in alveolar epithelial cells essentially controls the amount of alveolar fluid that should be kept at an appropriate level for normal gas exchange. The epithelial Na + transport is generally mediated through two steps: (1) the entry step of Na + via epithelial Na + channel (ENaC) at the apical membrane and (2) the extrusion step of Na + via the Na +, K +-ATPase at the basolateral membrane. In general, the Na + entry via ENaC is the rate-limiting step. Therefore, the regulation of ENaC plays an essential role in control of blood pressure and normal gas exchange. In this paper, we discuss two major factors in ENaC regulation: (1) activity of individual ENaC and (2) number of ENaC located at the apical membrane.

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          Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.

          C M Canessa, L Schild, G. Buell … (1994)
          The amiloride-sensitive epithelial sodium channel constitutes the rate-limiting step for sodium reabsorption in epithelial cells that line the distal part of the renal tubule, the distal colon, the duct of several exocrine glands, and the lung. The activity of this channel is upregulated by vasopressin and aldosterone, hormones involved in the maintenance of sodium balance, blood volume and blood pressure. We have identified the primary structure of the alpha-subunit of the rat epithelial sodium channel by expression cloning in Xenopus laevis oocytes. An identical subunit has recently been reported. Here we identify two other subunits (beta and gamma) by functional complementation of the alpha-subunit of the rat epithelial Na+ channel. The ion-selective permeability, the gating properties and the pharmacological profile of the channel formed by coexpressing the three subunits in oocytes are similar to that of the native channel.
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            Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination.

            O. Staub, I Gautschi, T. Ishikawa … (1997)
            The epithelial Na+ channel (ENaC), composed of three subunits (alpha beta gamma), plays a critical role in salt and fluid homeostasis. Abnormalities in channel opening and numbers have been linked to several genetic disorders, including cystic fibrosis, pseudohypoaldosteronism type I and Liddle syndrome. We have recently identified the ubiquitin-protein ligase Nedd4 as an interacting protein of ENaC. Here we show that ENaC is a short-lived protein (t1/2 approximately 1 h) that is ubiquitinated in vivo on the alpha and gamma (but not beta) subunits. Mutation of a cluster of Lys residues (to Arg) at the N-terminus of gamma ENaC leads to both inhibition of ubiquitination and increased channel activity, an effect augmented by N-terminal Lys to Arg mutations in alpha ENaC, but not in beta ENaC. This elevated channel activity is caused by an increase in the number of channels present at the plasma membrane; it represents increases in both cell-surface retention or recycling of ENaC and incorporation of new channels at the plasma membrane, as determined by Brefeldin A treatment. In addition, we find that the rapid turnover of the total pool of cellular ENaC is attenuated by inhibitors of both the proteasome and the lysosomal/endosomal degradation systems, and propose that whereas the unassembled subunits are degraded by the proteasome, the assembled alpha beta gamma ENaC complex is targeted for lysosomal degradation. Our results suggest that ENaC function is regulated by ubiquitination, and propose a paradigm for ubiquitination-mediated regulation of ion channels.
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              Epithelial sodium channel regulated by aldosterone-induced protein sgk.

              J. Wang, P E Buse, F Verrey … (1999)
              Sodium homeostasis in terrestrial and freshwater vertebrates is controlled by the corticosteroid hormones, principally aldosterone, which stimulate electrogenic Na+ absorption in tight epithelia. Although aldosterone is known to increase apical membrane Na+ permeability in target cells through changes in gene transcription, the mechanistic basis of this effect remains poorly understood. The predominant early effect of aldosterone is to increase the activity of the epithelial sodium channel (ENaC), although ENaC mRNA and protein levels do not change initially. Rather, the open probability and/or number of channels in the apical membrane are greatly increased by unknown modulators. To identify hormone-stimulated gene products that modulate ENaC activity, a subtracted cDNA library was generated from A6 cells, a stable cell line of renal distal nephron origin, and the effect of candidates on ENaC activity was tested in a coexpression assay. We report here the identification of sgk (serum and glucocorticoid-regulated kinase), a member of the serine-threonine kinase family, as an aldosterone-induced regulator of ENaC activity. sgk mRNA and protein were strongly and rapidly hormone stimulated both in A6 cells and in rat kidney. Furthermore, sgk stimulated ENaC activity approximately 7-fold when they were coexpressed in Xenopus laevis oocytes. These data suggest that sgk plays a central role in aldosterone regulation of Na+ absorption and thus in the control of extracellular fluid volume, blood pressure, and sodium homeostasis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Biomed Biotechnol
                Journal ID (publisher-id): JBB
                Title: Journal of Biomedicine and Biotechnology
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1110-7243
                ISSN (Electronic): 1110-7251
                Publication date (Print): 2011
                Publication date (Electronic): 17 October 2011
                Volume: 2011
                Electronic Location Identifier: 978196
                Affiliations
                1Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
                2Japan Institute for Food Education and Health, Heian Jogakuin (St. Agnes') University, Kyoto 602-8013, Japan
                3Shin-Koiwa Clinic, Tokyo 124-0023, Japan
                4Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
                5Department of Physiology, Osaka Medical College, Takatsuki 569-8686, Japan
                Author notes

                Academic Editor: Val J. Watts

                Article
                DOI: 10.1155/2011/978196
                PMC ID: 3196915
                PubMed ID: 22028593
                SO-VID: 4af586da-1951-4223-bdf7-8f78ca7f33fa
                Copyright © Copyright © 2011 Yoshinori Marunaka et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 21 May 2011
                Date revision received : 9 July 2011
                Date accepted : 3 August 2011
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Molecular medicine
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                ScienceOpen disciplines: Molecular medicine

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