Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 48, Pages 12834-12844Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3896-08.2008
Keywords
RNA editing; ADAR; serotonin receptor 2C; energy homeostasis; melanocortin 4C receptor; obesity
Categories
Funding
- National Institutes of Health
- Juvenile Diabetes Research Foundation
- Commonwealth Universal Research Enhancement Program
- Pennsylvania Department of Health
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RNA editing that converts adenosine to inosine replaces the gene-encoded Ile, Asn, and Ile (INI) of serotonin [5-hydroxytryptamine (5-HT)] receptor 2C (5-HT2CR) with Val, Gly, and Val (VGV). Up to 24 different 5-HT2CR isoforms are detected in different brain regions (Burns et al., 1997; Fitzgerald et al., 1999; Wang et al., 2000). To elucidate the physiological significance of 5-HT2CR mRNA editing, we derived mutant mouse lines harboring a knock-in INI or VGV allele, resulting in sole expression of one of two extremely different editing isoforms 5-HT2CR-INI (editing blocked) or-VGV (fully edited). Although INI mice grew normally, VGV mice had a severely reduced fat mass, despite compensatory hyperphagia, as a result of constitutive activation of the sympathetic nervous system and increased energy expenditure. Furthermore, serotonergic neurotransmission was oversensitized in VGV mice, most likely because of the increased cell surface expression of VGV receptors. Melanocortin 4 receptor (MC4R) regulates energy homeostasis (Balthasar et al., 2005; Heisler et al., 2006; Lam et al., 2008), and Mc4r(-/-)mice are obese because of hyperphagia and reduced energy expenditure (Huszar et al., 1997). However, the elevated energy expenditure of VGV mice could not be rescued in the Mc4r(-/-)background, indicating the presence of a distinct signaling pathway mediated via 5-HT2CR-VGV that dominates the MC4R-dependent pathway in control of energy expenditure. Our results highlight the importance of regulated 5-HT2CR mRNA editing, because dysregulation could result in the pathological consequences such as growth retardation seen in VGV mice.
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