Abstract
Transcripts encoding 5-HT2C receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5-HT2C-VGV, exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5-HT2C-VGV receptors in brain to determine the in vivo consequences of altered editing. Using mice solely expressing the 5-HT2C-VGV receptor (VGV/Y), we demonstrate reduced G-protein coupling efficiency and high-affinity agonist binding of brain 5-HT2C-VGV receptors. However, enhanced behavioral sensitivity to a 5-HT2C receptor agonist was also seen in mice expressing 5-HT2C-VGV receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5-HT2C-VGV receptors had greater sensitivity to a 5-HT2C 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-HT2C receptor binding sites in the brains of mice solely expressing 5-HT2C-VGV receptors. We conclude that 5-HT2C-VGV receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5-HT2C receptor binding site density in mice solely expressing the VGV isoform. 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 function of the receptor.
Highlights
The serotonin 2C (5-HT2C) receptor modulates a number of neurophysiological functions including appetite, mood, sexual behavior, and locomotion (Buhot, 1997; Olivier et al, 1998; Giorgetti and Tecott, 2004; Millan, 2005), and is implicated in the etiology of psychiatric disorders such as depression, anxiety, anorexia-nervosa, and obsessive-compulsive disorder (Griebel, 1995; Delgado and Moreno, 1998; Berg et al, 2008; Flaisher-Grinberg et al, 2008)
We conclude that 5-HT2C-VGV receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5-HT receptor binding site density in mice solely expressing theVGV isoform.These findings suggest that RNA editing may regulate the density of 5-HT2C receptor binding sites in brain
RNA editing is an enzymatic process that converts adenosine to inosine at five nucleotide positions in the 5th exon of the 5-HT2C receptor RNA transcript, encoding the second intracellular loop, a region important for G-protein coupling
Summary
The serotonin 2C (5-HT2C) receptor modulates a number of neurophysiological functions including appetite, mood, sexual behavior, and locomotion (Buhot, 1997; Olivier et al, 1998; Giorgetti and Tecott, 2004; Millan, 2005), and is implicated in the etiology of psychiatric disorders such as depression, anxiety, anorexia-nervosa, and obsessive-compulsive disorder (Griebel, 1995; Delgado and Moreno, 1998; Berg et al, 2008; Flaisher-Grinberg et al, 2008). Variation in 5-HT2C receptor RNA editing has been implicated in a variety of neuropsychiatric disorders, with the most reproducible finding being an increase in RNA editing in brains of suicide victims (Niswender et al, 2001; Gurevich et al, 2002; Dracheva et al, 2008a,b) Despite these findings, defining the in vivo functional consequences of 5-HT2C receptor RNA editing has been limited due to technical constraints presented by the immense diversity of receptor RNA isoforms in brain. We further show that changes in the degree of editing significantly alters the density of receptor binding sites within the brain, suggesting that the pattern of protein isoforms, and the inferred overall function of the receptor protein, may not reflect the pattern of RNA isoforms This finding has significant ramifications for basic as well as clinical studies of disease-related alterations in RNA editing of the 5-HT2C receptor
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