Glucocorticoids Distinctively Modulate the CFTR Channel with Possible Implications in Lung Development and Transition into Extrauterine Life
Fig 11
Effect of GCs on CFTR expression and activity in alveolar and airway epithelial cells.
A: Postnatal alveolar cells predominantly exhibit Na+ absorption. Na+ enters the alveolar cells through apical Na+ channels like ENaC and is actively extruded basolaterally by the Na,K-ATPase. Thereby an osmotic gradient is generated that drives fluid absorption from the alveolar lumen into the interstitium. Apical CFTR is suggested to mainly absorb Cl- in postnatal alveolar cells. GCs were shown to markedly reduce CFTR mRNA expression and activity in alveolar cells. B: In airway epithelial cells, Cl- enters the basolateral membrane across NKCC1 and Na+ is actively extruded by the Na,K-ATPase. K+ channels recycle K+ at the basolateral side hyperpolarizing the membrane which represents the driving force for apical Cl- extrusion through CFTR and Ca2+-dependent Cl- channels (CaCC). Vectorial Cl- transport drives water secretion into the airways. GCs reduced CFTR mRNA expression, but increased CFTR activity which supposedly depends on the proposed kinase pathway. GCs activate the PI3K leading to the generation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Phosphoinositide-dependent kinase-1 (PDK1) is activated and further phosphorylates and activates SGK1. SGK1 in turn interacts with the ubiquitin-ligase Nedd4-2 reducing the affinity of Nedd4-2 for CFTR. Thereby the endocytic retrieval of CFTR is inhibited and CFTR plasma membrane abundance increased. PCL = periciliary liquid layer. Not all potentially important ion transporters and kinases are included in this schematic model.