Hormone-induced expression of the epithelial sodium channel in human airway cells

Respiratory distress syndrome and pulmonary oedema often result in poor health and in the worst case scenario, death. Several studies have proposed that the eventual resolution of these dangerous conditions is due to active sodium reabsorption through the epithelial sodium channel (ENaC), which is crucial for lung fluid clearance. Although clinical prognosis can be improved by using glucocorticoid hormones to augment the ENaC-dependent removal of liquid from the lungs, we still require a better understanding of the underlying mechanism in order to improve treatments in the future. This thesis, therefore explores the role of serum / glucocorticoid-inducible protein kinase 1 (SGK1) and protein kinase A (PKA) in the responses of hormone-stimulated H441 human airway cells. Dexamethasone, a synthetic glucocorticoid hormone, is thought to evoke expression of the gene encoding SGK1 and, to become catalytically active, this gene product must then be phosphorylated via TORC2 and PDK1, protein kinases activated via the P13-kinase pathway. Once activated, SGK1 appears to exert control over the surface abundance of ENaC subunits by phosphorylation, and thus inactivating, a ubiquitin ligase (Nedd4-2), that normally mediate the withdrawal of ENaC subunits from the plasma membrane. Protein kinase A (PKA) may contribute to this control mechanism by also phosphorylating Nedd4-2. In order to clarify the way in which these pathways contribute to glucocorticoid-induced lung liquid clearance, the present thesis has explored the effects of dexamethasone and / or PKA activation upon the overall / surface expression of ENaC subunits, the activities of SGK1 and PKA and the phosphorylation status of physiologically-important residues within Nedd4-2 itself.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Dundee

Year dc:date.issued

2013

Author dc:creator

• Ismail, Noor

Advisor dc:contributor.advisor

• Land, Stephen

• Epithelial Na+ Channel
• SGK1
• H441 cell line
• Protein Kinase A
• NEDD4-2
• Ubiquitin
• Glucocorticoid
• PI3 kinase
• TORC2

Language dc:language

eng

Identifier

oai:discovery.dundee.ac.uk:studenttheses/b0adffc7-eac8-49c4-b0ed-35cea636a3a9

OAI identifier oai:identifier

oai:discovery.dundee.ac.uk:studenttheses/b0adffc7-eac8-49c4-b0ed-35cea636a3a9