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- W2204384758 abstract "Investigations of how ligands specifically bind to dopamine receptors and how receptorinteracting proteins associate with dopamine receptors are important to the development of novel therapeutic strategies and the understanding of function of the central nervous system. The goals of my dissertation are to identify the structural determinants of pharmacological specificity between D1 and D2 dopamine receptors and to identify the arrestin-binding sites of D2 and D3 dopamine receptors.* To achieve the first goal, I hypothesized that pharmacological differentiation between D1 and D2 dopamine receptors results from interactions of selective ligands with nonconserved residues lining the binding pocket. Amino acid residues in the D2 receptor were mutated to the corresponding aligned residues in the D1 receptor and vice versa and the receptors were expressed in human embryonic kidney (HEK) 293 cells. The affinities of the mutant receptors for D 1and Dz-selective antagonists were determined by radio ligand binding, followed by receptor homology modeling and ligand docking. I identified not only two residues that contribute to differential ligand binding profiles by interacting directly with ligands, but also one residue that affects D1/D2 pharmacological selectivity presumably by affecting the overall shape of binding pocket. To investigate the arrestin-binding sites of D2 and D3 dopamine receptors, first, the second and third intracellular loops (IC2 and IC3) ofboth receptor subtypes were examined for their direct interactions with purified arrestin-2 and-3 using glutathinone-S-transferase (GST) pull-down assays. Secondly, chimeric, truncation, and substitution mutants were constructed to test their ability to bind purified arrestin-3. Data from these studies indicate that higher binding affinity of arrestin-3 to D2 receptor over D3 * D1, D2, D3, D4 and D5 with subscripted numerals, genetic subtypes Dl or Dl-like and D2 or D2-like, pharmacological subtypes" @default.
- W2204384758 created "2016-06-24" @default.
- W2204384758 creator A5031286677 @default.
- W2204384758 date "2006-01-01" @default.
- W2204384758 modified "2023-09-23" @default.
- W2204384758 title "Structure and function of dopamine receptors : ligand binding and arrestin binding" @default.
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