基因行为查识别了一个孤儿的抗阿片类药物系统
Dandan Wang1, Hannah M Stoveken1, Stefano Zucca1
1Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
Science (New York, N.Y.)
|August 17, 2019
概括
研究人员发现G蛋白结合受体139 (GPR139),是一种抗阿片类药物点. 在小鼠中删除GPR139改变了吗啡的效果,这表明GPR139可以提高阿片类药物的安全性并减少滥用潜力.
科学领域:
- 神经科学
- 遗传学
- 药理学
背景情况:
- 阿片类药物是有效的止痛药,向μ-阿片类受体 (MOR).
- 由于滥用潜力,阿片类药物成仍然是一个重大的公共卫生问题.
- 影响阿片类药物反应的遗传因素需要进一步阐明.
研究的目的:
- 开发一个全动物查平台,以无偏见地发现阿片类药物反应调节剂.
- 确定新基因和调节阿片类信号和行为的途径.
- 探索已确定目标的治疗潜力,以提高阿片类药物安全性.
主要方法:
- 在*Caenorhabditis elegans*中利用前进基因来选影响阿片类反应的突变.
- 开发了一个全动物行为平台来进行高通量基因选.
- 在哺乳动物模型 (小鼠) 中研究了已识别的基因,包括GPR139的功能.
- 研究了GPR139与MOR的同时表达,与MOR的结合,以及其对G蛋白信号传递的影响.
主要成果:
- 鉴定G蛋白结合受体139 (GPR139) 是一种具有抗阿片类活性的保存孤儿受体.
- 在对阿片类药物敏感的神经回路中,GPR139与MOR共同表达.
- GPR139与MOR结合并抑制MOR介导的G蛋白信号传递.
- 在小鼠中删除GPR139调节了吗啡诱导的止痛,奖励和戒断症状.
- 在GPR139淘汰小鼠中显示了阿片类药物诱导的神经元抑制的增强.
结论:
- GPR139作为MOR信号的负调节剂,表现出抗阿片类药物的特性.
- GPR139是提高阿片类药物安全性和缓解成的潜在治疗点.
- *C. elegans*平台提供了一个可扩展的方法来发现G蛋白合受体信号原理.
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