dc.creator | Olaghere da Silva, Uade | |
dc.date.accessioned | 2020-08-21T20:58:51Z | |
dc.date.available | 2010-02-09 | |
dc.date.issued | 2010-02-09 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-02012010-015023 | |
dc.identifier.uri | http://hdl.handle.net/1803/10509 | |
dc.description.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. | |
dc.format.mimetype | application/pdf | |
dc.subject | RNA editing | |
dc.subject | Receptor | |
dc.subject | 5-HT | |
dc.title | In Vivo Functional Consequences of the Fully Edited 5-HT2C-VGV Receptor | |
dc.type | dissertation | |
dc.contributor.committeeMember | Randy Blakely | |
dc.contributor.committeeMember | Ariel Deutch | |
dc.contributor.committeeMember | Sanika Chirwa | |
dc.contributor.committeeMember | Elaine Sanders-Bush | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Neuroscience | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2010-02-09 | |
local.embargo.lift | 2010-02-09 | |
dc.contributor.committeeChair | Craig Kennedy | |