title: Organization of the ENaC-regulatory machinery.
abstract: The control of fluid and electrolyte homeostasis in vertebrates requires the integration of a diverse set of signaling inputs, which control epithelial Na(+) transport, the principal ionic component of extracellular fluid. The key site of regulation is a segment of the kidney tubules, frequently termed the aldosterone-sensitive distal nephron, wherein the epithelial Na(+) channel (or ENaC) mediates apical ion entry. Na(+) transport in this segment is strongly regulated by the salt-retaining hormone, aldosterone, which acts through the mineralocorticoid receptor (MR) to influence the expression of a selected set of target genes, most notably the serine-threonine kinase SGK1, which phosphorylates and inhibits the E3 ubiquitin ligase Nedd4-2. It has long been known that ENaC activity is tightly regulated in vertebrate epithelia. Recent evidence suggests that SGK1 and Nedd4-2, along with other ENaC-regulatory proteins, physically associate with each other and with ENaC in a multi-protein complex. The various components of the complex are regulated by diverse signaling networks, including steroid receptor-, PI3-kinase-, mTOR-, and Raf-MEK-ERK-dependent pathways. In this review, we focus on the organization of the targets of these pathways by multi-domain scaffold proteins and lipid platforms into a unified complex, thereby providing a molecular basis for signal integration in the control of ENaC.
authors.affiliation: Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Soundararajan
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.forename: David
authors.initials: D
authors.lastname: Pearce
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D053503:Epithelial Sodium Channels; D034521:Nuclear Matrix-Associated Proteins; D000450:Aldosterone