Epithelial Na + channel activity in human airway epithelial cells

The role of serum and glucocorticoid-inducible kinase 1

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

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

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

Fingerprint

Epithelial Sodium Channels
Human Activities
Glucocorticoids
Epithelial Cells
serum-inducible kinase
Protein Kinases
Dexamethasone
Phosphotransferases

Keywords

  • 3-phosphatidylinositol phosphate kinase
  • epithelial Na channel
  • H441 cells
  • pulmonary Na absorption
  • serum and glucocorticoid-regulated kinase 1
  • TORC2

ASJC Scopus subject areas

  • Pharmacology

Cite this

Epithelial Na + channel activity in human airway epithelial cells : The role of serum and glucocorticoid-inducible kinase 1. / Watt, Gordon B.; Ismail, Noor Akmal Shareela; Caballero, Agustin Garcia; Land, Stephen C.; Wilson, Stuart M.

In: British Journal of Pharmacology, Vol. 166, No. 4, 06.2012, p. 1272-1289.

Research output: Contribution to journalArticle

Watt, Gordon B. ; Ismail, Noor Akmal Shareela ; Caballero, Agustin Garcia ; Land, Stephen C. ; Wilson, Stuart M. / Epithelial Na + channel activity in human airway epithelial cells : The role of serum and glucocorticoid-inducible kinase 1. In: British Journal of Pharmacology. 2012 ; Vol. 166, No. 4. pp. 1272-1289.
@article{0beb67da43ed4bec8651f3d7541109e5,
title = "Epithelial Na + channel activity in human airway epithelial cells: The role of serum and glucocorticoid-inducible kinase 1",
abstract = "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.",
keywords = "3-phosphatidylinositol phosphate kinase, epithelial Na channel, H441 cells, pulmonary Na absorption, serum and glucocorticoid-regulated kinase 1, TORC2",
author = "Watt, {Gordon B.} and Ismail, {Noor Akmal Shareela} and Caballero, {Agustin Garcia} and Land, {Stephen C.} and Wilson, {Stuart M.}",
year = "2012",
month = "6",
doi = "10.1111/j.1476-5381.2012.01860.x",
language = "English",
volume = "166",
pages = "1272--1289",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Epithelial Na + channel activity in human airway epithelial cells

T2 - The role of serum and glucocorticoid-inducible kinase 1

AU - Watt, Gordon B.

AU - Ismail, Noor Akmal Shareela

AU - Caballero, Agustin Garcia

AU - Land, Stephen C.

AU - Wilson, Stuart M.

PY - 2012/6

Y1 - 2012/6

N2 - 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.

AB - 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.

KW - 3-phosphatidylinositol phosphate kinase

KW - epithelial Na channel

KW - H441 cells

KW - pulmonary Na absorption

KW - serum and glucocorticoid-regulated kinase 1

KW - TORC2

UR - http://www.scopus.com/inward/record.url?scp=84861316702&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861316702&partnerID=8YFLogxK

U2 - 10.1111/j.1476-5381.2012.01860.x

DO - 10.1111/j.1476-5381.2012.01860.x

M3 - Article

VL - 166

SP - 1272

EP - 1289

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 4

ER -