RNA splicing and editing modulation of 5-HT2C receptor function: relevance to anxiety and aggression in VGV mice
RNA splicing and editing modulation of 5-HT2C receptor function: relevance to anxiety and aggression in VGV mice
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DOI：
10.1038/mp.2012.171
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发表时间：
2013-06-01
影响因子：
11
通讯作者：
Mongeau, R.
中科院分区：
文献类型：
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作者：
Martin, C. B. P.;Ramond, F.;Mongeau, R.
5-羟色胺（2C）受体（5-HTR 2c）编辑，剪接和密度的变化在抑郁症和自杀等疾病中被发现，但解释5-HTR 2c功能变化的机制尚不清楚。因此，研究了仅表达5-HTR 2c的完全编辑的VGV同种型的小鼠，其中临床相关的行为变化与剪接和受体密度的改变相关。VGV小鼠在社交互动测试中对优先5-HTR 2c激动剂的反应显示出增强的焦虑样行为。近一半的相互作用对VGV同源物之间的战斗行为，而没有战斗发生在野生型（WT）小鼠。VGV小鼠对先天厌恶的超声波刺激也表现出明显的冻结行为增加。这种行为表型发生在一起减少脑5-HT营业额在压力。这些功能数据与5-HTR 2c mRNA剪接过程有关，除了全长受体（5-HTR 2c-Fl）外，还产生截短的蛋白质（5-HTR 2c-Tr）。5-HTR 2c-Tr mRNA在VGV小鼠的许多脑区中含量较低，而VGV小鼠的5-HTR 2c含量高于WT小鼠。荧光共振能量转移和生物发光共振能量转移研究表明，5-HTR 2c-Tr与5-HTR 2c-Fl相互作用，5-HTR 2c-Tr定位于内质网中，阻止5-HTR 2c-Fl到达质膜。因此，5-HTR 2c-Tr以浓度依赖性方式降低H-3-美舒麦角在质膜处与5-HTR 2c-Fl的结合，并且与编辑的5-HTR 2c-Fl的结合更强烈。这些结果表明，5-HTR 2c前mRNA编辑和剪接是通过5-HTR 2c-Tr的缺陷确定病理条件下5-HTR 2c水平增加的增强过程。
Changes in serotonin(2C) receptor (5-HTR2c) editing, splicing and density were found in conditions such as depression and suicide, but mechanisms explaining the changes in 5-HTR2c function are unknown. Thus, mice expressing only the fully edited VGV isoform of 5-HTR2c, in which clinically relevant behavioral changes are associated with alterations in splicing and receptor density, were studied. VGV mice displayed enhanced anxiety-like behavior in response to a preferential 5-HTR2c agonist in the social interaction test. Nearly half of interactions between pairs of VGV congeners consisted of fighting behaviors, whereas no fighting occurred in wild-type (WT) mice. VGV mice also exhibited a striking increase in freezing behaviors in reaction to an innately aversive ultrasonic stimulus. This behavioral phenotype occurred in conjunction with decreased brain 5-HT turnover during stress. These functional data were put in relation with the 5-HTR2c mRNA splicing process generating a truncated protein (5-HTR2c-Tr) in addition to the full-length receptor (5-HTR2c-Fl). 5-HTR2c-Tr mRNA was less abundant in many brain regions of VGV mice, which concomitantly had more 5-HTR2c than WT mice. Fluorescence resonance energy transfer and bioluminescence resonance energy transfer studies in transfected living HEK293T cells showed that 5-HTR2c-Tr interacts with 5-HTR2c-Fl. The 5-HTR2c-Tr was localized in the endoplasmic reticulum where it retained 5-HTR2c-Fl, preventing the latter to reach the plasma membrane. Consequently, 5-HTR2c-Tr decreased H-3-mesulergine binding to 5-HTR2c-Fl at the plasma membrane in a concentration-dependent manner and more strongly with edited 5-HTR2c-Fl. These results suggest that 5-HTR2c pre-mRNA editing and splicing are entwined processes determining increased 5-HTR2c levels in pathological conditions through a deficit in 5-HTR2c-Tr.