title: Epithelial Na⁺ channel activity in human airway epithelial cells: the role of serum and glucocorticoid-inducible kinase 1.
abstract: OBJECTIVE
  Glucocorticoids appear to control Na⁺ absorption in pulmonary epithelial cells via a mechanism dependent upon serum and glucocorticoid-inducible kinase 1 (SGK1), a kinase that allows control over the surface abundance of epithelial Na⁺ channel subunits (α-, β- and γ-ENaC). However, not all data support this model and the present study re-evaluates this hypothesis in order to clarify the mechanism that allows glucocorticoids to control ENaC activity.
  
  
  METHODS
  Electrophysiological studies explored the effects of agents that suppress SGK1 activity upon glucocorticoid-induced ENaC activity in H441 human airway epithelial cells, whilst analyses of extracted proteins explored the associated changes to the activities of endogenous protein kinase substrates and the overall/surface expression of ENaC subunits.
  
  
  RESULTS
  Although dexamethasone-induced (24 h) ENaC activity was dependent upon SGK1, prolonged exposure to this glucocorticoid did not cause sustained activation of this kinase and neither did it induce a coordinated increase in the surface abundance of α-, β- and γ-ENaC. Brief (3 h) exposure to dexamethasone, on the other hand, did not evoke Na⁺ current but did activate SGK1 and cause SGK1-dependent increases in the surface abundance of α-, β- and γ-ENaC.
  
  
  CONCLUSIONS
  Although glucocorticoids activated SGK1 and increased the surface abundance of α-, β- and γ-ENaC, these responses were transient and could not account for the sustained activation of ENaC. The maintenance of ENaC activity did, however, depend upon SGK1 and this protein kinase must therefore play an important but permissive role in glucocorticoid-induced ENaC activation.
authors.affiliation: Centre for Cardiovascular and Lung Research, Division of Medical Sciences, College of Medicine, Dentistry & Nursing, University of Dundee, Dundee, UK.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Watt
authors.forename: Noor A S
authors.initials: NA
authors.lastname: Ismail
authors.forename: Agustin Garcia
authors.initials: AG
authors.lastname: Caballero
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Land
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Wilson
mesh_terms: D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003907:Dexamethasone; D004791:Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D014157:Transcription Factors; D000099184:Serum-Glucocorticoid Regulated Kinases; C493245:CRTC2 protein, human; C507045:SCNN1A protein, human; C507048:SCNN1B protein, human; C507052:SCNN1G protein, human