Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 287, Issue 4, Pages L843-L851Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00340.2003
Keywords
epithelial sodium channel; glucocorticoids; airway epithelia; p38 mitogen-activated protein kinase
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Funding
- NHLBI NIH HHS [R01 HL071664, HL-71664] Funding Source: Medline
- NIDDK NIH HHS [R01 DK054348, DK-54348] Funding Source: Medline
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H441 cells, a bronchiolar epithelial cell line, develop a cAMP-regulated benzamil-sensitive Na+ transport pathway on permeable supports (Itani OA, Auerbach SD, Husted RF, Volk KA, Ageloff S, Knepper MA, Stokes JB, Thomas CP. Am J Physiol Lung Cell Mol Physiol 282: L631 - L641, 2002). To understand the molecular basis for the stimulation of Na+ transport, we delineated the role of specific intracellular pathways and examined the effect of cAMP on alphabetagamma-epithelial Na+ channel (ENaC) and sgk1 expression. Na+ transport increases within 5 min of cAMP stimulation and is sustained for > 24 h. The sustained effect of cAMP on Na+ transport is abolished by LY-294002, an inhibitor of phosphatidylinositol 3-kinase, by H89, an inhibitor of PKA, or by SB-202190, an inhibitor of p38 MAP kinase. The sustained effect of cAMP was associated with increases in alpha-ENaC mRNA and protein but without a detectable increase in betagamma-ENaC and sgk1. The early effect of cAMP on Na+ transport is brefeldin sensitive and is mediated via PKA. These results are consistent with a model where the early effect of cAMP is to increase trafficking of Na+ channels to the apical cell surface whereas the sustained effect requires the synthesis of alpha-ENaC.
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