title: Impact of RNA editing on functions of the serotonin 2C receptor in vivo.
abstract: Transcripts encoding 5-HT(2C) receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5-HT(2C-VGV), exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5-HT(2C-VGV) receptors in brain to determine the in vivo consequences of altered editing. Using mice solely expressing the 5-HT(2C-VGV) receptor (VGV/Y), we demonstrate reduced G-protein coupling efficiency and high-affinity agonist binding of brain 5-HT(2C-VGV) receptors. However, enhanced behavioral sensitivity to a 5-HT(2C) receptor agonist was also seen in mice expressing 5-HT(2C-VGV) receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5-HT(2C-VGV) receptors had greater sensitivity to a 5-HT(2C) inverse agonist/antagonist enhancement of dopamine turnover relative to wild-type mice. These behavioral and biochemical results are most likely explained by increases in 5-HT(2C) receptor binding sites in the brains of mice solely expressing 5-HT(2C-VGV) receptors. We conclude that 5-HT(2C-VGV) receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5-HT(2C) receptor binding site density in mice solely expressing the VGV isoform. These findings suggest that RNA editing may regulate the density of 5-HT(2C) receptor binding sites in brain. We further caution that the pattern of 5-HT(2C) receptor RNA isoforms may not reflect the pattern of protein isoforms, and hence the inferred overall function of the receptor.
authors.affiliation: Center for Molecular Neuroscience, Vanderbilt University School of Medicine Nashville, TN, USA.
authors.forename: Uade B
authors.initials: UB
authors.lastname: Olaghere da Silva
authors.forename: Michael V
authors.initials: MV
authors.lastname: Morabito
authors.forename: Clinton E
authors.initials: CE
authors.lastname: Canal
authors.forename: David C
authors.initials: DC
authors.lastname: Airey
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Emeson
authors.forename: Elaine
authors.initials: E
authors.lastname: Sanders-Bush