RNA editing of the human serotonin 5-Hydroxytryptamine 2C receptor silences constitutive activity
RNA editing of the human serotonin 5-Hydroxytryptamine 2C receptor silences constitutive activity
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DOI：
10.1074/jbc.274.14.9472
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发表时间：
1999-04-02
影响因子：
4.8
通讯作者：
Sanders-Bush, E
中科院分区：
文献类型：
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作者：
Niswender, CM;Copeland, SC;Sanders-Bush, E
编码5-羟色胺2C（5-HT 2C）受体（5-HT 2CR）的RNA转录物在多达五个特定位点经历腺苷至肌苷RNA编辑事件。与大鼠脑相比，人脑样品分别在156、158和160位表达更高水平的编码氨基酸缬氨酸-丝氨酸-缬氨酸（5-HT 2C-VSV）和缬氨酸-甘氨酸-缬氨酸（5-HT 2C-VGV）的RNA转录物。未编辑的人受体的激动剂刺激（5-HT 2C-INI）和在NIH-3 T3成纤维细胞中稳定表达的编辑的5-HT 2C-VSV和5-HT 2C-VGV受体变体证明了鸟嘌呤能激动剂对编辑的受体的效力较低。竞争结合实验揭示了仅对5-HT 2C-INI受体的鸟嘌呤核苷酸敏感的5-羟色胺高亲和力状态;与编辑受体结合的高亲和力激动剂的丧失表明RNA编辑产生独特的5-HT（2C）R，其与G蛋白偶联的效率较低。编辑亚型的G蛋白偶联减少主要是由于未编辑的5-HT 2CR的组成型活性沉默。激动剂效力和组成性活性的差异表明，不同编辑的5-HT（2C）R对多巴胺能配体表现出不同的反应，并进一步暗示RNA编辑代表了一种控制多巴胺能突触生理信号传导的新机制。
RNA transcripts encoding the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor (5-HT2CR) undergo adenosine-to-inosine RNA editing events at up to five specific sites. Compared with rat brain, human brain samples expressed higher levels of RNA transcripts encoding the amino acids valine-serine-valine (5-HT2C-VSV) and valine-glycine-valine (5-HT2C-VGV) at positions 156, 158, and 160, respectively. Agonist stimulation of the nonedited human receptor (5-HT2C-INI) and the edited 5-HT2C-VSV and 5-HT2C-VGV receptor variants stably expressed in NIH-3T3 fibroblasts demonstrated that serotonergic agonists were less potent at the edited receptors, Competition binding experiments revealed a guanine nucleotide-sensitive serotonin high affinity state only for the 5-HT2C-INI receptor; the loss of high affinity agonist binding to the edited receptor demonstrates that RNA editing generates unique 5-HT(2C)Rs that couple less efficiently to G proteins. This reduced G protein coupling for the edited isoforms is primarily due to silencing of the constitutive activity of the nonedited 5-HT2CR. The distinctions in agonist potency and constitutive activity suggest that different edited 5-HT(2C)Rs exhibit distinct responses to serotonergic ligands and further imply that RNA editing represents a novel mechanism for controlling physiological signaling at serotonergic synapses.