Date of Award

Summer 8-2009

Degree Type

Restricted Access Thesis

Degree Name

Master of Science

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Dr. John A. Schetz

Abstract

This work examines the contribution of transmembrane segments two and three to the activation state of the D2 dopamine receptor by using ligand probes which are highly sensitive to substitutions at specific amino acid positions within this microdomain. Specifically, D2 receptors were modified by substitution of one to three specific amino acids with the corresponding amino acids of the D4 receptor to enhance the binding of D4 selective 1,4-disubstituted aromatic piperidines/piperazines. The ability of these ligands to elicit G protein mediated inhibition of cyclic adenosine monophosphate was then tested. Modification of all three amino acid residues was found to modify ligand function at the D2 receptor to match the function elicited at the D4 receptor. Additionally, the modification of specific ligand interactions with the D2-V2.61F receptor in the presence of sodium provides evidence for transmembrane segment repositioning in the inactive state of G protein coupled receptors.

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