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Title page for ETD etd-02012010-015023


Type of Document Dissertation
Author Olaghere da Silva, Uade
Author's Email Address uade.dasilva@vanderbilt.edu
URN etd-02012010-015023
Title In Vivo Functional Consequences of the Fully Edited 5-HT2C-VGV Receptor
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Craig Kennedy Committee Chair
Ariel Deutch Committee Member
Elaine Sanders-Bush Committee Member
Randy Blakely Committee Member
Sanika Chirwa Committee Member
Keywords
  • RNA editing
  • Receptor
  • 5-HT
Date of Defense 2009-12-17
Availability unrestricted
Abstract
Transcripts encoding 5HT2C receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5HT2C-VGV, exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5HT2C-VGV receptors in brain to determine the in vivo consequences of altered editing. Due to a surprising lack of ligand affinity data in mice, we first established the selectivity of several 5-HT2 receptor ligands in mice. Using mice solely expressing the 5HT2C-VGV (VGV/Y) receptor, we demonstrate reduced G-protein coupling efficiencies and high-affinity agonist binding of brain 5HT2C-VGV receptors. However, enhanced behavioral sensitivity to a 5HT2C receptor agonist was also seen in mice expressing 5HT2C-VGV receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5HT2C-VGV receptors had enhanced sensitivity to 5HT2C inverse agonist/antagonist enhancement of dopamine turnover relative to wild-type mice. These behavioral and biochemical results are most likely explained by massive increases in receptor binding sites in the brains of mice solely expressing 5HT2C-VGV receptors. We conclude that 5-HT2C-VGV receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in receptor binding site density. These findings suggest that RNA editing may regulate the density of 5-HT2C receptor binding sites in brain. We further caution that the pattern of 5-HT2C receptor RNA isoforms may not reflect the pattern of protein isoforms, and hence the inferred overall receptor functionality.
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