The NMDA receptor is the subject of intense study due to its critical role in many neuronal processes and neuropathologies. This receptor is modulated by a wide variety of endogenous and exogenous agents, including reducing and oxidizing (redox) agents. Despite a wealth of physiological information, details of the structural basis of modulation are only beginning to emerge. It has been proposed that the amino terminal domain (ATD) of NMDA receptor subunits may serve as a modulatory domain, as several agents appear to have sites of action in this region of the receptor. NR1/NR2A receptors contain cysteines in the ATD of both NR1 and NR2 that confer unique redox sensitivity to these receptors; however, the ATD redox sensitivity of NR1/NR2A receptors remains largely unexplored. The goal of this dissertation was to explore the impact of reducing and oxidizing agents on NMDA receptor function, focusing on the amino terminal domain redox sites. Here we demonstrate that a clinically efficacious neuroprotective agent, ebselen, is active as an oxidizing agent of the NMDA receptor. Additionally, these studies demonstrate a novel modulation of NR1/NR2A redox mutants by the polyamine spermine and explore a relationship between redox and spermine modulation of NR1/NR2A mutant receptors.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-09292003-021236 |
| Date | 08 December 2003 |
| Creators | Herin, Greta Ann |
| Contributors | Stephen D. Meriney, Ian J. Reynolds, Zuo-Zhong Wang, Elias Aizenman, Jon W. Johnson |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-09292003-021236/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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