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研究筛查抗阿片类药物的新靶点
作者:小柯机器人 发布时间:2019/9/20 12:19:33

美国斯克里普斯研究所Kirill A. Martemyanov和Brock Grill合作,通过遗传行为筛查鉴定抗阿片类药物的新靶点。这一研究成果2019年9月20日发表在《科学》上。 

研究者构建了一个全动物行为平台,用于无偏倚的发现影响阿片类药物反应的基因。利用秀丽隐杆线虫的前向遗传学,研究人员鉴定了一种具有抗阿片类药物活性的保守孤儿受体GPR139。GPR139在阿片样物质敏感的脑回路中与MOR共表达,并与MOR结合,抑制异源三聚体鸟嘌呤核苷酸结合蛋白(G蛋白)的信号传导。小鼠中GPR139的缺失增强了对阿片类药物诱导的神经元放电的抑制,从而调节吗啡诱导的镇痛、奖励和戒断。因此,GPR139可能是提高阿片类药物安全性的有用靶点。这些结果还证明,秀丽隐杆线虫有作为G蛋白偶联受体信号传导筛选平台的潜力。

据了解,阿片类药物靶向μ-阿片受体(MOR)以减缓难以忍受的疼痛,但它们的成瘾特性可导致这类药物的严重滥用。

附:英文原文

Title: Genetic behavioral screen identifies an orphan anti-opioid system

Author: Dandan Wang, Hannah M. Stoveken, Stefano Zucca, Maria Dao, Cesare Orlandi, Chenghui Song, Ikuo Masuho, Caitlin Johnston, Karla J. Opperman, Andrew C. Giles, Matthew S. Gill, Erik A. Lundquist, Brock Grill, Kirill A. Martemyanov

Issue&Volume:Volume 365 Issue 6459

Abstract: 

Opioids target the μ-opioid receptor (MOR) to produce unrivaled pain management, but their addictive properties can lead to severe abuse. We developed a whole-animal behavioral platform for unbiased discovery of genes influencing opioid responsiveness. Using forward genetics in Caenorhabditis elegans, we identified a conserved orphan receptor, GPR139, with anti-opioid activity. GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds to MOR, and inhibits signaling to heterotrimeric guanine nucleotide–binding proteins (G proteins). Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing to modulate morphine-induced analgesia, reward, and withdrawal. Thus, GPR139 could be a useful target for increasing opioid safety. These results also demonstrate the potential of C. elegans as a scalable platform for genetic discovery of G protein–coupled receptor signaling principles.

DOI: 10.1126/science.aau2078

Source:https://science.sciencemag.org/content/365/6459/1267

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037