Epithelial Na+ channel activity in human airway epithelial cells: the role of serum and glucocorticoid‐inducible kinase 1

• Published in: British journal of pharmacology Vol. 166; no. 4; pp. 1272 - 1289
• Main Authors: Watt, Gordon B, Ismail, Noor AS, Caballero, Agustin Garcia, Land, Stephen C, Wilson, Stuart M
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2012; Nature Publishing Group
• Subjects: 3‐phosphatidylinositol phosphate kinase; Biological and medical sciences; Cell Line; Dexamethasone - pharmacology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; epithelial Na+ channel; Epithelial Sodium Channels - metabolism; Glucocorticoids - pharmacology; H441 cells; Humans; Immediate-Early Proteins - antagonists & inhibitors; Immediate-Early Proteins - metabolism; Kinases; Medical sciences; Membrane Potentials - drug effects; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinase - metabolism; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation - drug effects; Protein Processing, Post-Translational - drug effects; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein Subunits - metabolism; pulmonary Na+ absorption; Research Papers; Respiratory Mucosa - drug effects; Respiratory Mucosa - enzymology; Respiratory Mucosa - metabolism; serum and glucocorticoid‐regulated kinase 1; Signal Transduction - drug effects; Sodium; Time Factors; TORC2; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Up-Regulation - drug effects; Phosphates; H441 cells; Biological fluid; pulmonary Na; TORC2; Lung; channel; Ionic channel; Respiratory system; Glucocorticoid; Respiratory tract; 3-phosphatidylinositol phosphate kinase; Phosphatidylinositol; Absorption; Serum; Human; epithelial Na; Enzyme; Transferases; In vitro; Sodium; Kinase; Epithelial cell; serum and glucocorticoid-regulated kinase 1; Pharmacokinetics
• DOI: 10.1111/j.1476-5381.2012.01860.x
• ISSN: 0007-1188; 1476-5381

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.