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Int. J. Mol. Sci. 2017, 18(8), 1807; doi:10.3390/ijms18081807

Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone

Center for Pediatric Research Leipzig, Division of Neonatology, University of Leipzig, 04103 Leipzig, Germany
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Received: 5 July 2017 / Revised: 10 August 2017 / Accepted: 17 August 2017 / Published: 19 August 2017
(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)
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Abstract

Impairment of mucociliary clearance with reduced airway fluid secretion leads to chronically inflamed airways. Cystic fibrosis transmembrane conductance regulator (CFTR) is crucially involved in airway fluid secretion and dexamethasone (dexa) has previously been shown to elevate CFTR activity in airway epithelial cells. However, the pathway by which dexa increases CFTR activity is largely unknown. We aimed to determine whether the increase of CFTR activity by dexa is achieved by non-genomic signaling and hypothesized that the phosphoinositide 3-kinase (PI3K) pathway is involved in CFTR stimulation. Primary rat airway epithelial cells and human bronchial submucosal gland-derived Calu-3 cells were analyzed in Ussing chambers and kinase activation was determined by Western blots. Results demonstrated a critical involvement of PI3K and protein kinase B (AKT) signaling in the dexa-induced increase of CFTR activity, while serum and glucocorticoid dependent kinase 1 (SGK1) activity was not essential. We further demonstrated a reduced neural precursor cell expressed, developmentally downregulated 4-like (NEDD4L) ubiquitin E3 ligase activity induced by dexa, possibly responsible for the elevated CFTR activity. Finally, increases of CFTR activity by dexa were demonstrated within 30 min accompanied by rapid activation of AKT. In conclusion, dexa induces a rapid stimulation of CFTR activity which depends on PI3K/AKT signaling in airway epithelial cells. Glucocorticoids might thus represent, in addition to their immunomodulatory actions, a therapeutic strategy to rapidly increase airway fluid secretion. View Full-Text
Keywords: cystic fibrosis transmembrane conductance regulator; glucocorticoids; dexamethasone; airway; phosphoinositide 3-kinase; serum and glucocorticoid dependent kinase 1; protein kinase B; neural precursor cell expressed, developmentally downregulated 4-like cystic fibrosis transmembrane conductance regulator; glucocorticoids; dexamethasone; airway; phosphoinositide 3-kinase; serum and glucocorticoid dependent kinase 1; protein kinase B; neural precursor cell expressed, developmentally downregulated 4-like
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MDPI and ACS Style

Bossmann, M.; Ackermann, B.W.; Thome, U.H.; Laube, M. Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone. Int. J. Mol. Sci. 2017, 18, 1807.

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