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REGULATORY MECHANISMS OF GAMMA-AMINOBUTYRIC ACID
TRANSPORTER 1 IN THE RAT BRAIN
by
Jia Hu
_____________________________________________________________________
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 2007
Copyright 2007 Jia Hu
Object Description
| Title | Regulatory mechanisms of gamma-aminobutyric acid transporter 1 in the rat brain |
| Author | Hu, Jia |
| Author email | whujia@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2007-10-18 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-11-02 |
| Advisor (committee chair) | Quick, Michael W. |
| Advisor (committee member) |
Okamoto, Curtis Ko, Chien-Ping McKemy, David Butler, Samantha |
| Abstract | Chemical synapses are the principal locations where signals are transmitted between neurons. The transmission of this chemical signal is largely influenced by the action of neurotransmitter transporters which contribute to synaptic transmission by removing neurotransmitters from the synaptic cleft and thus terminating the synaptic signal. Abnormal activities of neurotransmitter transporters are associated with a variety of brain disorders. Therefore, drugs targeting neurotransmitter transporters play an important role in treating these diseases.; Since only the neurotransmitter transporters present on the plasma membrane are able to take up synaptically localized transmitters, it is critical to maintain a proper number of surface transporters. Recent advances in transporter biochemistry and molecular biology have provided substantial insights into transporter structure and function, intracellular transporter trafficking, and the association of transporters with other cellular proteins. All of these areas of research have been shown to be important in how neurons maintain an appropriate repertoire of transporter proteins at the plasma membrane. In this dissertation, I provide answers to three separate questions that examine the regulatory mechanisms underlying the subcellular trafficking of neurotransmitter transporters. First, how does the structure of transporter proteins affect their intracellular trafficking? We identified critical residues and motifs for GAT1 oligomerization and trafficking by constructing site-direct mutations. Second, how do protein phosphorylation states interact to regulate intracellular trafficking of GAT1? We found that serine and tyrosine phosphorylation of GAT1 are mutually exclusive and that their relative abundance determines GAT1 trafficking. Third, how do transporter substrates regulate the trafficking kinetics of GAT1? We demonstrated that transporter substrates regulate GAT1 trafficking in a time-dependent manner, by changing both trafficking rates and the number of transporter molecules that are available to traffic.; The finding in these studies provide a model of GAT1 trafficking that may shed light on the subcellular trafficking of other neurotransmitter transporters. Such understanding may help us decode the signals transmitted at chemical synapses and resolve pathological processes related to brain disorders. In addition, our model offers insights to the pharmacokinetics of clinical drugs targeting GAT1, which may improve drug efficacy when administrated to patients. |
| Keyword | phosphorylation; structure; substrate; regulation; GAT1; GABA |
| 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-m904 |
| Contributing entity | University of Southern California |
| Rights | Hu, Jia |
| 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-Hu-20071102 |
| Archival file | uscthesesreloadpub_Volume23/etd-Hu-20071102.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Full text | REGULATORY MECHANISMS OF GAMMA-AMINOBUTYRIC ACID TRANSPORTER 1 IN THE RAT BRAIN by Jia Hu _____________________________________________________________________ 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 2007 Copyright 2007 Jia Hu |
