The influence of subunit composition and expression system on recombinant glycine receptor pharmacology : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2002]
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| Subjects: |
| Abstract: | ABSTRACT: Glycine receptors (GlyRs) are thought to primarily exist in the adult mammalian spinal cord where they mediate inhibitory neurotransmission. Our data suggests the presence of glycine receptors in the adult forebrain as well. However, the function and pharmacology of these receptors remains unclear. Immunohistchemical, electrophysiological and molecular biological techniques were utilized to study glycine receptor localization in the forebrain and evaluate pharmacological profiles between GlyR forebrain and spinal cord isoforms. The immunohistochemistry suggests GlyRs have a restricted distribution in the forebrain. Electrophysiological results indicate that the neuronal isoforms may be the GlyRα₂β heteromer; different than the GlyRα₁β found in the adult spinal cord. For example, the relative efficacy of the partial agonists was reduced in cells expressing the putative forebrain isoform compared to the spinal cord isoform. However, the relative efficacy was also greatly influenced by the expression system in which the receptors were expressed. These pharmacologic differences between expression systems were not due to expression level or transfection efficiency but rather inherent characteristics within each system. The pharmacological profile was similar between cell lines that share morphological characteristics. Furthermore, intracellular constituents associated with cytoskeleton appear to play a major role in determining receptor partial agonist pharmacology. The work presented here will help shatter the long-standing belief that adult strychnine-sensitive glycine receptors are confined to the spinal cord in the central nervous system. GlyRs expressed in the adult forebrain exist in isolated populations, the basolateral amygdala for example, and are unique from the spinal cord isoform, both pharmacologically and at the molecular level. These novel characteristics make basolateral amygdala GlyRs potential therapeutic targets for such ailments as anxiety disorders. As a further consideration, the therapeutic utility of a receptor may not only depend on the isoform or subunit composition, but also the intracellular environment in which it exists. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Graduate School of Biomedical Sciences of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy December 2002." Approved as to style and content by: Brian A. McCool, Gerald D. Frye, William H. Griffith, III, Rajesh C. Miranda, George C. Y. Chiou. |
| Physical Description: | xiv, 155 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 125-154). |