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The structure of loop 2 is important for agonist and ethanol sensitivity in glycine and GABA Alpha receptors

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Title	The structure of loop 2 is important for agonist and ethanol sensitivity in glycine and GABA Alpha receptors
Author	Perkins, Daya
Author email	diyer@usc.edu; dayaperkins@gmail.com
Degree	Doctor of Philosophy
Document type	Dissertation
Degree program	Molecular Pharmacology & Toxicology
School	School of Pharmacy
Date defended/completed	2010-03-18
Date submitted	2010
Restricted until	Unrestricted
Date published	2010-05-07
Advisor (committee chair)	Alkana, Ronald L.
Advisor (committee member)	Davies, Daryl L. Brinton, Roberta Diaz McKemy, David
Abstract	Glycine receptors (GlyRs) and gamma-aminobutyric type A receptors (GABA_ARs) are recognized as the primary mediators of neuronal inhibition in the central nervous system (CNS). There is a large body of evidence that implicates GABA_ARs in the behavioral effects of ethanol and building evidence supports the notion that ethanol acting on GlyRs causes at least a subset of its behavioral effects. For several decades, GlyRs and GABA_ARs have been studied at the molecular level for targets for ethanol action. Despite the advances in understanding the effects of ethanol in vivo and in vitro, the precise molecular sites and mechanisms of action for ethanol in ligand-gated ion channels (LGICs) in general, and in GlyRs and GABA_ARs specifically, are just now starting to become understood. The present dissertation focuses on studies we conducted that address this issue using molecular biology, pressure antagonism, electrophysiology and molecular modeling strategies to probe, identify and model the initial molecular sites and mechanisms of ethanol action in GlyRs and GABA_ARs. Specifically, this work focuses on the Loop 2 region in the extracellular domain of GlyRs and GABA_ARs and (1) Provides evidence that position 52 in Loop 2 is a target for ethanol action and antagonism in GlyRs; (2) Demonstrates that the structural bases for the actions of ethanol and pressure on this common target are different and (3) Provides strong evidence that the structure of Loop 2 in GlyRs, GABA_ARs and possibly across LGICs may be a key factor in controlling the sensitivity of these receptors to ethanol. Collectively, the studies provide new models and mechanisms for ethanol action in GlyRs and GABA_ARs.
Keyword	electrophysiology; ethanol; GABA; glycine; molecular models; 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-m3035
Rights	Perkins, Daya
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-Perkins-3546
Archival file	uscthesesreloadpub_Volume17/etd-Perkins-3546.pdf

Title	Page 1
Full text	THE STRUCTURE OF LOOP 2 IS IMPORTANT FOR AGONIST AND ETHANOL SENSITIVITY IN GLYCINE AND GABAA RECEPTORS by Daya Perkins 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 (MOLECULAR PHARMACOLOGY AND TOXICOLOGY) May 2010 Copyright 2010 Daya Perkins

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