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NEW UNDERSTANDING OF RHODOPSIN IN RETINAL DEGENERATION
AND HIGH GAIN PHOSPHORYLATION
by
Jiayan Chen
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
(NEUROSCIENCE)
December 2006
Copyright 2006 Jiayan Chen
Object Description
| Title | New understanding of rhodopsin in retinal degeneration and high gain phosphorylation |
| Author | Chen, Jiayan |
| Author email | jiayanch@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2006-10-31 |
| Date submitted | 2006 |
| Restricted until | Unrestricted |
| Date published | 2006-11-22 |
| Advisor (committee chair) | Chen, Jeannie |
| Abstract | Through the experiments described in this thesis, I strived to obtain a better understanding the function of rhodopsin in retinal degeneration and light adaptation. Over 100 rhodopsin mutation alleles have been associated with autosomal dominant retinitis pigmentosa (ADRP), a blindness disorder that affects one in 3000 people globally. These mutations appear to cause photoreceptor cell death through diverse molecular mechanisms. We show that Lys296Glu (K296E), a rhodopsin mutation associated with ADRP, forms a stable complex with arrestin that is toxic to mouse rod photoreceptors. This cell death pathway appears to be conserved from flies to mammals. Accumulation of stable rhodopsin/arrestin complexes in the inner segment may be an important mechanism for triggering cell death in the mammalian photoreceptor cells. Abnormal turnover of rhodopsin mutants could also underlie a mechanism leading to cell death. In order to investigate rhodopsin turnover rate, rhodopsin was tagged with a special fluorescent reporter Timer, which changes color with the function of time, to report rhodopsin turnover activity.; Phosphorylation of rhodopsin is a required step in signal deactivation. Rhodopsin exhibits high-gain phosphorylation in vitro whereby hundred-fold molar excess of phosphates are incorporated into the rhodopsin pool per mole of activated rhodopsin. The extent, by which high-gain phosphorylation occurs in the intact mammalian photoreceptor cell, and the molecular mechanism underlying this reaction in vivo, are not known. Trans-phosphorylation is a proposed mechanism for high-gain phosphorylation whereby rhodopsin kinase, upon phosphorylating the activated receptor, continues to phosphorylate nearby non-activated rhodopsin. We utilized two different transgenic mouse models: K296E and cone short-wavelength opsin (S-opsin), and found that trans-phosphorylation occurs in the intact photoreceptor cell. Trans-phosphorylation may play an important role in light adaptation by decreasing transduction gain and thereby extending the range of the rod response under certain steady-state lighting conditions. |
| Keyword | rhodopsin; retinal degeneration; photoreceptor |
| 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 |
| Type | texts |
| Legacy record ID | usctheses-m191 |
| Rights | Chen, Jiayan |
| 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-Chen-20061122 |
| Archival file | uscthesesreloadpub_Volume29/etd-Chen-20061122.pdf |
Description
| Title | Page 1 |
| Full text | NEW UNDERSTANDING OF RHODOPSIN IN RETINAL DEGENERATION AND HIGH GAIN PHOSPHORYLATION by Jiayan Chen 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 (NEUROSCIENCE) December 2006 Copyright 2006 Jiayan Chen |
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