Small molecule drug screening in Drosophila identifies the 5HT2A receptor as a feeding modulation target.
Small molecule drug screening in Drosophila identifies the 5HT2A receptor as a feeding modulation target.
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果蝇小分子药物筛选将 5HT2A 受体确定为摄食调节靶点
DOI：
10.1038/srep02120
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发表时间：
2013
影响因子：
4.6
通讯作者：
Vosshall, Leslie B
中科院分区：
文献类型：
--
作者：
Gasque, Gabriel;Conway, Stephen;Huang, Juan;Rao, Yi;Vosshall, Leslie B
饮食行为失调会导致肥胖，影响全球10%的成年人口，每年造成近300万人死亡。尽管这对社会造成了负担，但我们目前缺乏有效的药物治疗选择来调节食欲。我们使用果蝇幼虫开发了一种高通量的全生物体筛选药物，调节食物摄入量。在对3630种小分子的筛选中，我们发现血清素（5-羟色胺或5-HT）受体拮抗剂美替平是一种有效的厌食药物。使用基于细胞的测定，我们表明，metitepine是所有五个果蝇5-HT受体的拮抗剂。我们筛选了这些受体的果蝇突变体，发现5-羟色胺受体5-HT 2A是美替平抑制摄食的唯一分子靶点。这些结果强调了控制食欲的分子机制的保守性，并提供了一种无偏见的全生物体药物筛选方法，以确定调节食物摄入的新药和分子途径。
Dysregulation of eating behavior can lead to obesity, which affects 10% of the adult population worldwide and accounts for nearly 3 million deaths every year. Despite this burden on society, we currently lack effective pharmacological treatment options to regulate appetite. We used Drosophila melanogaster larvae to develop a high-throughput whole organism screen for drugs that modulate food intake. In a screen of 3630 small molecules, we identified the serotonin (5-hydroxytryptamine or 5-HT) receptor antagonist metitepine as a potent anorectic drug. Using cell-based assays we show that metitepine is an antagonist of all five Drosophila 5-HT receptors. We screened fly mutants for each of these receptors and found that serotonin receptor 5-HT2A is the sole molecular target for feeding inhibition by metitepine. These results highlight the conservation of molecular mechanisms controlling appetite and provide a method for unbiased whole-organism drug screens to identify novel drugs and molecular pathways modulating food intake.