Serotonin 5-HT2C receptor RNA editing alters receptor basal activity:: Implications for serotonergic signal transduction
Serotonin 5-HT2C receptor RNA editing alters receptor basal activity:: Implications for serotonergic signal transduction
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DOI：
10.1046/j.1471-4159.1999.731711.x
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发表时间：
1999-10-01
影响因子：
4.7
通讯作者：
Niswander, CM
中科院分区：
文献类型：
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作者：
Herrick-Davis, K;Grinde, E;Niswander, CM
评价大鼠和人5-羟色胺5-HT 2C受体亚型在COS-7细胞中磷酸肌醇产生的激动剂非依赖性激活。未编辑的同种型（5-HT 2C-INI）显示出最大的基础活性，刺激磷酸肌醇的产生是完全编辑的同种型（5-HT 2C-VGV）的四倍。检测的所有其他亚型均显示中等水平的基础活性。受体表达水平降低50%，基础活性也相应降低。5-HT通过5-HT 2C-INI受体刺激磷酸肌醇产生是基础水平的两倍，通过5-HT 2C-VGV受体刺激磷酸肌醇产生是基础水平的八倍，但产生了类似的磷酸肌醇最大水平，5-HT竞争[H-3]美舒麦角碱与5-HT 2C-INI的结合最适合双位点分析，K-H = 7.6 nM和K-L = 160 nM，而5-HT 2C-VGV最佳地拟合单位点模型，Ki = 163 nM。[H-3]5-HT标记了[H-3]美舒麦角碱标记的5-HT 2C-INI受体总数的36%，但仅标记了12%的5-HT 2C-VGV受体。[H-3]5-HT K-D值从5-HT 2C-INI的5.1 nM增加至5-HT 2C-VGV的20 nM。[H-3]两种亚型的美舒麦角碱K-D值相同，磷酸肌醇产生的5-HT EC 50值从5-HT 2C-INI的6.1 nM增加至5-HT 2C-VGV的30 nM。这些结果表明，RNA编辑降低了5-HT 2C受体的基础活性、激动剂亲和力和效力，表明RNA编辑可能在调节多巴胺能信号转导和对药物治疗的反应中发挥作用。
Rat and human serotonin 5-HT2C receptor isoforms were evaluated for agonist-independent activation of inositol phosphate production in COS-7 cells. The nonedited isoform (5-HT2C-INI) displayed the greatest basal activity, stimulating inositol phosphate production fourfold over the fully edited isoform (5-HT2C-VGV). All of the other isoforms tested displayed intermediate levels of basal activity. Decreasing receptor expression levels by 50% produced a parallel decrease in basal activity. 5-HT stimulated inositol phosphate production twofold over basal levels through the 5-HT2C-INI receptor and eightfold over basal levels through the 5-HT2C-VGV receptor but produced similar maximal levels of inositol phosphate, 5-HT competition for [H-3]mesulergine binding to 5-HT2C-INI best fit a two-site analysis with K-H = 7.6 nM and K-L = 160 nM, whereas 5-HT2C-VGV best fit a one-site model with K-i = 163 nM. [H-3]5-HT labeled 36% of the total population of 5-HT2C-INI receptors labeled by [H-3]mesulergine but only 12% of 5-HT2C-VGV receptors. [H-3]5-HT K-D values increased from 5.1 nM for 5-HT2C-INI to 20 nM for 5-HT2C-VGV. [H-3]Mesulergine K-D values were the same for both isoforms, 5-HT EC50 values for inositol phosphate production increased from 6.1 nM for 5-HT2C-INI to 30 nM for 5-HT2C-VGV. These results demonstrate that RNA editing decreases 5-HT2C receptor basal activity, agonist affinity, and potency, indicating that RNA editing may play a role in regulating serotonergic signal transduction and response to drug therapy.