Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass.
Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass.
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DOI：
10.1523/jneurosci.3896-08.2008
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发表时间：
2008-11-26
期刊：
影响因子：
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通讯作者：
Nishikura K
中科院分区：
文献类型：
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作者：
Kawahara Y;Grimberg A;Teegarden S;Mombereau C;Liu S;Bale TL;Blendy JA;Nishikura K
将腺苷转化为肌苷的RNA编辑用瓦尔、Gly和瓦尔（VGV）替换5-羟色胺（5-HT）受体2C（5-HT 2CR）的基因编码的Ile、Asn和Ile（INI）。在不同的脑区检测到多达24种不同的5-HT 2CR亚型。为了阐明5-HT 2CR mRNA编辑的生理学意义，我们衍生了携带敲入INI或VGV等位基因的突变小鼠系，导致两种极其不同的编辑同种型5-HT 2CR-INI（编辑阻断）或-VGV（完全编辑）之一的唯一表达。尽管INI小鼠正常生长，但VGV小鼠的脂肪量严重减少，尽管存在代偿性摄食过多，这是由于交感神经系统的组成性激活和能量消耗增加。此外，在VGV小鼠中，多巴胺能神经传递过度敏感，最可能是由于VGV受体的细胞表面表达增加。黑素皮质素4受体（MC 4 R）调节能量稳态，Mc 4 r −/−小鼠由于摄食过多和能量消耗减少而肥胖。然而，VGV小鼠升高的能量消耗不能在Mc 4 r −/−背景下被挽救，表明存在通过5-HT 2CR-VGV介导的独特信号传导途径，该途径在控制能量消耗中主导MC 4 R依赖性途径。我们的研究结果强调了受调控的5-HT 2CR mRNA编辑的重要性，因为失调可能导致病理后果，如VGV小鼠中观察到的生长迟缓。
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. 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, in spite of compensatory hyperphagia, due to constitutive activation of the sympathetic nervous system and increased energy expenditure. Furthermore, serotonergic neurotransmission was oversensitized in VGV mice, most likely due to the increased cell surface expression of VGV receptors. Melanocortin 4 receptor (MC4R) regulates energy homeostasis, and Mc4r−/− mice are obese due to hyperphagia and reduced energy expenditure. 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, as dysregulation could result in the pathological consequences such as growth retardation seen in VGV mice.