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BIOCHEMICAL MODIFICATIONS AND REGULATION OF THE GASTRIC
H,K-ATPASE
by
Gerald Kenji Nagatani
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
May 2009
Copyright 2009 Gerald Kenji Nagatani
Object Description
| Title | Biochemical modifications and regulation of the gastric H,K-ATPase |
| Author | Nagatani, Gerald Kenji |
| Author email | nagatani@usc.edu; nagatani@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2009-01-29 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-05-04 |
| Advisor (committee chair) | Okamoto, Curtis T. |
| Advisor (committee member) |
Haworth, Ian S. Farley, Robert A. |
| Abstract | The α/β heterodimeric gastric H,K-ATPase is the enzyme responsible for gastric HCl secretion by the parietal cell. It is an integral membrane protein of the extensive system of intracellular membranes known as tubulovesicles of resting parietal cells, and it is trafficked to the apical plasma membrane upon stimulation by a regulated fusion of tubulovesicles with the apical membrane. There are, however, further mechanisms that may regulate HCl secretion, and these will be explored in this doctoral dissertation. Very little is known about the direct regulation of the H,K-ATPase and the mechanisms that regulate the enzymatic activity of the enzyme. Furthermore, little has been reported about certain posttranslational modifications that may occur on the H,K-ATPase, specifically ubiquitination and glutathiolation, which may have implications in the regulation of the activity of the H,K-ATPase within the parietal cell. The regulation of membrane recycling, particularly the tight packing of tubulovesicles in a resting parietal cell is also poorly understood.; Here we present evidence for the direct regulation of H,K-ATPase enzymatic activity by phosphatidylinositol phosphates and their metabolites. Two posttranslational modifications, ubiquitination and glutathiolation, were also determined to play a potential role in H,K-ATPase regulation. Ubiquitin generally targets cellular proteins for degradation via the lysosome or proteasome. Glutathione potentially serves several functions when modified to the cysteine residues of proteins, including protection from irreversible oxidation. These biochemical modifications and potential regulatory mechanisms of H,K-ATPase activity are novel findings.; Finally, a potential regulatory mechanism of parietal cell tubulovesicular membrane structure and function in vitro was discovered to be dependent on pH. Tubulovesicles were found to reversibly cluster in vitro at low pH, and H,K-ATPase activity was inhibited. A majority of the original H,K-ATPase activity was able to be restored upon reversal of the clustering, suggesting that the clustering may be physiologically significant.; By gaining an understanding of regulatory mechanisms and biochemical modifications of the gastric H,K-ATPase in vitro, we can better understand how it may function in vivo. This research has the potential to lead to novel drug targets for the H,K-ATPase that may aid in the control of acid secretion -- a problem from which millions worldwide suffer. |
| Keyword | H,K-ATPase; proton pump; parietal cell; tubulovesicles; phosphoinositides; ubiquitin; ubiquitination; glutathione; glutathiolation |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2169 |
| Rights | Nagatani, Gerald Kenji |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Nagatani-2671 |
| Archival file | uscthesesreloadpub_Volume44/etd-Nagatani-2671.pdf |
Description
| Title | Page 1 |
| Full text | BIOCHEMICAL MODIFICATIONS AND REGULATION OF THE GASTRIC H,K-ATPASE by Gerald Kenji Nagatani A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHARMACEUTICAL SCIENCES) May 2009 Copyright 2009 Gerald Kenji Nagatani |
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