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The regulation of selective and nonselective Na⁺ conductances in H441 human airway epithelial cells

Lung Membrane Transport Group, Division of Maternal and Child Health Sciences, College of Medicine, Dentistry and Nursing, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom

Submitted 22 June 2007 ; accepted in final form 25 February 2008

Analysis of membrane currents recorded from hormone-deprived H441 cells showed that the membrane potential (V_m) in single cells (approximately –80 mV) was unaffected by lowering [Na⁺]_o or [Cl^–]_o, indicating that cellular Na⁺ and Cl^– conductances (G_Na and G_Cl, respectively) are negligible. Although insulin (20 nM, 24 h) and dexamethasone (0.2 µM, 24 h) both depolarized V_m by 20 mV, the response to insulin reflected a rise in G_Cl mediated via phosphatidylinositol 3-kinase (PI3K) whereas dexamethasone acted by inducing a serum- and glucocorticoid-regulated kinase 1 (SGK1)-dependent rise in G_Na. Although insulin stimulation/PI3K-P110 expression did not directly increase G_Na, these maneuvers augmented the dexamethasone-induced conductance. The glucocorticoid/SGK1-induced G_Na in single cells discriminated poorly between Na⁺ and K⁺ (P_Na/P_K 0.6), was insensitive to amiloride (1 mM), but was partially blocked by LaCl₃ (La³⁺; 1 mM, 80%), pimozide (0.1 mM, 40%), and dichlorobenzamil (15 µM, 15%). Cells growing as small groups, on the other hand, expressed an amiloride-sensitive (10 µM), selective G_Na that displayed the same pattern of hormonal regulation as the nonselective conductance in single cells. These data therefore 1) confirm that H441 cells can express selective or nonselective G_Na (14, 48), 2) show that these conductances are both induced by glucocorticoids/SGK1 and subject to PI3K-dependent regulation, and 3) establish that cell-cell contact is vitally important to the development of Na⁺ selectivity and amiloride sensitivity.

epithelial Na⁺ channel; serum- and glucocorticoid regulated kinase 1; phosphatidylinositol 3-kinase; H441 cells; pulmonary Na⁺ absorption

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