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The Journal of Neuroscience, November 26, 2008, 28(48):12834-12844; doi:10.1523/JNEUROSCI.3896-08.2008

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Cellular/Molecular
Dysregulated Editing of Serotonin 2C Receptor mRNAs Results in Energy Dissipation and Loss of Fat Mass

Yukio Kawahara,¹ Adda Grimberg,² Sarah Teegarden,³ Cedric Mombereau,⁴ Sui Liu,¹ Tracy L. Bale,³ Julie A. Blendy,⁴ and Kazuko Nishikura¹

¹The Wistar Institute, ²Department of Pediatric Endocrinology, The Children's Hospital of Philadelphia, Abramson Research Center, ³Department of Animal Biology, University of Pennsylvania, and ⁴Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Kazuko Nishikura, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Email: kazuko{at}wistar.org

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-HT_2CR) with Val, Gly, and Val (VGV). Up to 24 different 5-HT_2CR 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-HT_2CR 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-HT_2CR-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-HT_2CR-VGV that dominates the MC4R-dependent pathway in control of energy expenditure. Our results highlight the importance of regulated 5-HT_2CR mRNA editing, because dysregulation could result in the pathological consequences such as growth retardation seen in VGV mice.

Key words: RNA editing; ADAR; serotonin receptor 2C; energy homeostasis; melanocortin 4C receptor; obesity

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Received Aug. 4, 2008; revised Oct. 3, 2008; accepted Oct. 21, 2008.

Correspondence should be addressed to Dr. Kazuko Nishikura, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Email: kazuko{at}wistar.org

This article has been cited by other articles:

				M. Barak, E. Y. Levanon, E. Eisenberg, N. Paz, G. Rechavi, G. M. Church, and R. Mehr Evidence for large diversity in the human transcriptome created by Alu RNA editing Nucleic Acids Res., November 1, 2009; 37(20): 6905 - 6915. [Abstract] [Full Text] [PDF]

				C. M. Doe, D. Relkovic, A. S. Garfield, J. W. Dalley, D. E.H. Theobald, T. Humby, L. S. Wilkinson, and A. R. Isles Loss of the imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour Hum. Mol. Genet., June 15, 2009; 18(12): 2140 - 2148. [Abstract] [Full Text] [PDF]

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