Impact of RNA editing on functions of the serotonin 2C receptor in vivo.
Impact of RNA editing on functions of the serotonin 2C receptor in vivo.
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DOI：
10.3389/neuro.23.001.2010
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发表时间：
2010
影响因子：
4.3
通讯作者：
Sanders-Bush E
中科院分区：
文献类型：
--
作者：
Olaghere da Silva UB;Morabito MV;Canal CE;Airey DC;Emeson RB;Sanders-Bush E
编码5-HT 2C受体的转录物通过RNA编辑进行转录后修饰，产生多达24种蛋白质亚型。在重组细胞中，完全编辑的同种型5-HT 2C-VGV表现出钝化的G蛋白偶联和降低的组成型活性。本研究检查了大脑中5-HT 2C-VGV受体的信号转导特性，以确定改变编辑的体内后果。使用仅表达5-HT 2C-VGV受体（VGV/Y）的小鼠，我们证明了降低的G蛋白偶联效率和脑5-HT 2C-VGV受体的高亲和力激动剂结合。然而，在表达5-HT 2C-VGV受体的小鼠中也观察到对5-HT 2C受体激动剂的增强的行为敏感性，这是一个意外的发现，因为G蛋白偶联变钝。此外，表达5-HT 2C-VGV受体的小鼠相对于野生型小鼠对多巴胺周转的5-HT 2C反向激动剂/拮抗剂增强具有更大的敏感性。这些行为和生化结果最有可能解释为仅表达5-HT 2C-VGV受体的小鼠脑中5-HT 2C受体结合位点的增加。我们的结论是，5-HT 2C-VGV受体在大脑中的信号是钝化的，但这种缺陷被掩盖的5-HT 2C受体结合位点密度在小鼠单独表达VGV亚型显着增加。这些结果表明，RNA编辑可以调节脑中5-HT 2C受体结合位点的密度。我们进一步警告说，5-HT 2C受体RNA亚型的模式可能不反映蛋白质亚型的模式，因此推断的受体的整体功能。
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.
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影响因子：
4.7
作者：
Herrick-Davis, K;Grinde, E;Niswander, CM
通讯作者：
Niswander, CM
影响因子：
1.7
作者：
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通讯作者：
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影响因子：
64.8
作者：
Burns, CM;Chu, H;Emeson, RB
通讯作者：
Emeson, RB
影响因子：
4.7
作者：
Canal CE;Mahautmr KC;Cao C;Sanders-Bush E;Airey DC
通讯作者：
Airey DC
影响因子：
4.7
作者：
Di Matteo, V;Di Giovanni, G;Esposito, E
通讯作者：
Esposito, E