Concerted action of ENaC, Nedd4-2, and Sgk1 in transepithelial Na(+) transport.
The epithelial Na(+) channel (ENaC), located in the apical membrane of renal aldosterone-responsive epithelia, plays an essential role in controlling the Na(+) balance of extracellular fluids and hence blood pressure. As of now, ENaC is the only Na(+) transport protein for which genetic evidence exists for its involvement in the genesis of both hypertension (Liddle's syndrome) and hypotension (pseudohypoaldosteronism type 1). The regulation of ENaC involves a variety of hormonal signals (aldosterone, vasopressin, insulin), but the molecular mechanisms behind this regulation are mostly unknown. Two regulatory proteins have gained interest in recent years: the ubiquitin-protein ligase neural precursor cell-expressed, developmentally downregulated gene 4 isoform Nedd4-2, which negatively controls ENaC cell surface expression, and serum glucocorticoid-inducible kinase 1 (Sgk1), which is an aldosterone- and insulin-dependent, positive regulator of ENaC density at the plasma membrane. Here, we summarize present ideas about Sgk1 and Nedd4-2 and the lines of experimental evidence, suggesting that they act sequentially in the regulatory pathways governed by aldosterone and insulin and regulate ENaC number at the plasma membrane.
Kamynina
Elena
E
Institute of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland.
Staub
Olivier
O
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002135:Calcium-Binding Proteins / Q000502:physiology*; D004347:Drug Interactions; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins; D007668:Kidney / Q000378:metabolism; D008025:Ligases / Q000502:physiology*; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D002135:Calcium-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D008025:Ligases; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D015222:Sodium Channels; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human