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SITES OF ETHANOL ACTION IN P2X4 RECEPTORS
by
Maya S. Popova
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
December 2011
Copyright 2011 Maya S. Popova
Object Description
| Title | Sites of ethanol action in P2X4 receptors |
| Author | Popova, Maya S. |
| Author email | mpopova@usc.edu;mpopova@westernu.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2011-07-14 |
| Date submitted | 2011-08-30 |
| Date approved | 2011-08-31 |
| Restricted until | 2011-08-31 |
| Date published | 2011-08-31 |
| Advisor (committee chair) |
Davies, Daryl L. Alkana, Ronald L. |
| Advisor (committee member) | Petasis, Nicos A. |
| Abstract | P2X receptors (P2XRs) are a distinct family of ligand-gated ion channels that are widely found throughout the peripheral and central nervous systems. They are fast acting, cation-permeable ligand gated ion channels that are gated by synaptically released extracellular ATP. P2X4Rs are the most abundant P2XR subtype expressed in the CNS and the most ethanol sensitive P2X subtype identified to date. Recent findings suggested that P2X4Rs may play a role in alcohol intake and preference in rats. Although, a growing body of evidence suggests a role for P2XRs in ethanol modulation, the sites responsible for the action of ethanol in these receptors are just beginning to be studied and remain unresolved. The present dissertation addresses this issue by using electrophysiology, molecular biology and molecular modeling strategies to identify ethanol sensitive molecular sites in these receptors. This dissertation sets three interrelated hypothesis build on each other: 1) Chapter 2 tests the hypothesis that the ectodomain-TM interface contains residues that are important for the action of ethanol in P2X4Rs; 2) Chapter 3 tests the hypothesis that Trp46 plays a role in ethanol and/or IVM modulation and 3) Chapter 4 tests the hypothesis that residues within the TM1 domain (residues 29 to 49) are important for the action of ethanol in P2X4Rs. The findings identified several ethanol sensitive amino acid residues and support the notion that there are multiple sites for ethanol action in P2X4Rs. In addition these studies increased our understanding of the sites and mechanisms of agonist transduction in P2X4Rs. Overall, the findings significantly add to our knowledge regarding the molecular sites for ethanol action in P2X4Rs and suggest possible targets for drug development to prevent or treat ethanol abuse and dependence. |
| Keyword | alcohol; electrophysiology; ion channels; purinergic P2X4 receptors; xenopus oocytes ❧ |
| 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-m |
| Rights | Popova, Maya S. |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume71/etd-PopovaMaya-278.pdf |
Description
| Title | Page 1 |
| Full text | SITES OF ETHANOL ACTION IN P2X4 RECEPTORS by Maya S. Popova A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHARMACEUTICAL SCIENCES) December 2011 Copyright 2011 Maya S. Popova |
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