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Thesis (Ph. D.)--Oregon State University, 2010. / Printout. Includes bibliographical references (leaves 103-119). Also available on the World Wide Web.

Thesis (Ph. D.)--University of Missouri-Columbia, 2008. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on June 19, 2009) Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1966. / Typescript. Vita. Description based on print version record. Includes bibliographical references.

The epithelial sodium channel (ENaC) made up of α, β and γ subunits is located at the apical membrane of polarised epithelia and mediates transport of sodium ions into the cells. Tight control of ENaC function is essential for maintaining sodium homeostasis, blood volume and blood pressure. Controlling the number of active channels present at the cell surface appears to be critically important in regulating ENaC activity. The neural precursor cell expressed developmentally down-regulated gene 4 (Nedd4) family of proteins (eg. Nedd4-2) ubiquitinate ENaC and decrease its cell surface expression. The activity of Nedd4-2 is modulated by serum and glucocorticoid-induced kinase (SGK), which phosphorylates Nedd4-2 and increases cell surface expression of ENaC. The c̲o̲pper m̲etabolism gene M̲URR1 d̲omain 1 (COMMD1) protein is a recently identified ENaC binding partner and negative regulator of channel activity. Studies by other groups suggest that COMMD1 is also involved in the processes of intracellular protein trafficking and ubiquitin-dependent protein degradation. The aims of this study were 1). To characterise the interactions between COMMD1 and ENaC. 2). To identify the mechanism(s) by which COMMD1 down-regulates ENaC activity. Here protein-protein interaction studies were used to show that a recently identified conserved C-terminal domain (the COMM domain) in COMMD1 is essential for its binding to ENaC. The binding site for COMMD1 in βENaC was found to be located in its N-terminal domain. COMMD1 was shown to down-regulate ENaC by increasing ubiquitin modification of ENaC and by decreasing the cell surface population. COMMD1 was found to interact with SGK and formed a complex with SGK and Nedd4-2. Ussing chamber studies of Na⁺ transport showed that COMMD1 attenuated the stimulation of ENaC by SGK and abolished insulin-stimulated ENaC current in epithelial cells. Conversely, knock-down of COMMD1 increased ENaC current in mammalian epithelial cells. These data suggest that COMMD1 plays a role in regulating ENaC activity in epithelial cells and its effect is likely mediated via SGK. In addition COMMD1 was found to bind to the adaptor protein subunit [mu]2. Mutations in COMMD1 that disrupt its interaction with [mu]2 impair its ability to decrease cell surface expression of ENaC in Cos-7 cells, therefore COMMD1 may also have a role in the endocytosis of ENaC by linking cell surface ENaC to the clathrin-dependent endocytosis machinery. In summary, this study investigated the interactions between COMMD1 and ENaC and identified that the SGK/Nedd4-2 pathway is involved in the COMMD1-mediated ubiquitination and down-regulation of ENaC activity.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1982. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

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