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

Gordon B. Watt, Noor A. S. Ismail, Agustin Garcia Caballero, Stephen C. Land, Stuart M. Wilson

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    Abstract

    BACKGROUND AND PURPOSE Glucocorticoids appear to control 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 epithelia Na+ channel subunits (a-, ß- and y-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 a-, ß- and y-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 a-, ß- and y-ENaC. CONCLUSIONS AND IMPLICATIONS Although glucocorticoids activated SGK1 and increased the surface abundance of a-, ß- and y-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. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

    Original languageEnglish
    Pages (from-to)1272-1289
    Number of pages18
    JournalBritish Journal of Pharmacology
    Volume166
    Issue number4
    DOIs
    Publication statusPublished - Jun 2012

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