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.

Two Liters a Day Keep the Doctor Away? Considerations on the Pathophysiology of Suboptimal Fluid Intake in the Common Population

“…SGK1 stimulates the Na + ,K + ,2Cl - cotransporter NKCC [43], the NaCl cotransporter NCC [7, 37, 45, 49, 50], the Na + /H + exchanger NHE3 [37, 51-55] and the epithelial Na + channel ENaC [7] and thus augments renal tubular salt reabsorption [7, 37, 44, 46, 56]. Moreover, SGK1 stimulates salt appetite and thus salt intake [7, 43, 57].…”

“…SGK1 further participates in the regulation of the transcription factors nuclear factor kappa-B NFκB, p53, cAMP responsive element binding protein (CREB), activator protein-1 (AP-1), and forkhead transcription factor FKHR-L1 (FOXO3a) [33]. SGK1 participates in the orchestration of a wide variety of complex cellular functions including organization of the cytoskeleton [36], cell volume regulation [37], cell survival and cell proliferation [7, 38, 39], cell migration [40, 41], degranulation [36, 42], hormone release [37, 43], renal tubular Na + reabsorption [37, 43-46], renal tubular K + transport [47], gastric acid secretion [7, 37], as well as intestinal Na + and nutrient transport [43]. SGK1 may affect neuronal excitability [48], but the potential pathophysiological role of SGK1 in the brain remained hitherto elusive.…”

Activation of mTORC1 in Collecting Ducts Causes Hyperkalemia

“…Aldosterone binds to the nuclear mineralocorticoid receptor (MR) within the distal tubule, and the principal cells and activates Na + , K + -ATPase, thereby increasing Na + reabsorption into the blood and the electronegativity of the lumen and providing a more favorable driving force for the secretion of potassium through ROMK. 14,15 Aldosterone could also upregulate ENaC and ROMK in the apical membrane of CCD. Therefore, maintaining homeostasis and function of CCD is critical for potassium secretion.…”

A regulated NH2-terminal Sgk1 variant with enhanced function is expressed in the collecting duct

“…Sgk1 may stimulate ENaC-mediated Na ϩ transport via multiple pathways, each involving phosphorylation of intermediate substrates such as Nedd4 -2, WNK4, and Af9 (9,13,29). Furthermore, Sgk1 forms a multiprotein complex with ENaC, the ENaC regulatory complex (ERC), which includes adapter molecules, scaffold proteins, and signaling proteins (25). Sgk1 and Sgk1_i3 differ in their NH 2 termini which may regulate its interaction with various phosphoinositides, one or more of its intermediary substrates or with members of the ERC (19).…”