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J. Biol. Chem., Vol. 280, Issue 43, 35807-35814, October 28, 2005

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Rapid Effects of Dexamethasone on Intracellular pH and Na⁺/H⁺ Exchanger Activity in Human Bronchial Epithelial Cells^*

Valia A. Verrière, Darina Hynes, Sheila Faherty, James Devaney, Jean Bousquet, Brian J. Harvey, and Valérie Urbach1

From the INSERM U454, Centre Hospitalier Universitaire Arnaud de Villeneuve, 34295 Montpellier, France and Molecular Medicine Laboratories,Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland

Glucocorticoids have been shown to produce rapid nongenomic responses in airway epithelia. By using an intracellular pH (pH_i) spectrofluorescence imaging system and the NH₄ Cl acid-loading technique, we have shown that the synthetic glucocorticoid,dexamethasone, accelerated intracellular pH recovery after an acid load in a human bronchial epithelial cell line (16HBE14o^– cells). Exposure to NH₄Cl (20 mM) elicited an intracellular acidification, followed by a pH_i recovery. Inhibition of the Na⁺/H⁺ exchanger decreased the steady-state pH_i and antagonized the dexamethasone stimulation of pH_i regulation. The rapid effect of dexamethasone on pH_i was neither affected by the inhibitor of transcription, cycloheximide, nor by the classical glucocorticoid and mineralocorticoid receptors antagonists, RU486 and spironolactone, respectively. The dexamethasone effect on pH_i regulation was reduced by inhibitors of adenylate cyclase, cAMP-dependent protein kinase and mitogenactivated protein kinase (ERK1/2). By using a PepTag assay system and Western blotting, we have shown that dexamethasone stimulated cAMP-dependent protein kinase and mitogen-activated protein kinase activities. Taken together our results provide evidence for the rapid stimulation of Na⁺/H⁺ exchange activity by glucocorticoids in bronchial epithelial cells via a nongenomic mechanism involving cAMP-dependent protein kinase and mitogen-activated protein kinase ERK1/2 pathways.

Received for publication, June 17, 2005 , and in revised form, July 12, 2005.

^* This work was supported by INSERM, Vaincre la Mucoviscidose, the Regional Council of Languedoc-Roussillon (France), Wellcome Trust Grant 055695/Z/98/Z/CH/TG/JF, and the Higher Education Authority of Ireland PRTLI fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: INSERM U454, CHU A. de Villeneuve, 34295, Montpellier Cedex 05, France. Tel.: 04-67-33-59-31; Fax: 04-67-63-28-55; E-mail: urbach{at}montp.inserm.fr.

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