A natural variant and engineered mutation in a GPCR promote DEET resistance in C. elegans

Dennis Emily J.; Dobosiewicz May; Jin Xin; Duvall Laura B.; Hartman Philip S.; Bargmann Cornelia I; Vosshall Leslie B.

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A natural variant and engineered mutation in a GPCR promote DEET resistance in C. elegans

机译：GPCR中的自然变异和工程突变可促进秀丽隐杆线虫的DEET抗性

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DEET (N, N-diethyl-meta-toluamide) is a synthetic chemical identified by the US Department of Agriculture in 1946 in a screen for repellents to protect soldiers from mosquito-borne diseases(1,2). Since its discovery, DEET has become the world's most widely used arthropod repellent and is effective against invertebrates separated by millions of years of evolution-including biting flies(3), honeybees(4), ticks(5), and land leeches(3). In insects, DEET acts on the olfactory system(5-12) and requires the olfactory receptor co-receptor Orco(7,9-12), but exactly how it works remains controversial(13). Here we show that the nematode Caenorhabditis elegans is sensitive to DEET and use this genetically tractable animal to study the mechanism of action of this chemical. We found that DEET is not a volatile repellent, but instead interferes selectively with chemotaxis to a variety of attractant and repellent molecules. In a forward genetic screen for DEET-resistant worms, we identified a gene that encodes a single G protein-coupled receptor, str-217, which is expressed in a single pair of chemosensory neurons that are responsive to DEET, called ADL neurons. Mis-expression of str-217 in another chemosensory neuron conferred responses to DEET. Engineered str-217 mutants, and a wild isolate of C. elegans that carries a str-217 deletion, are resistant to DEET. We found that DEET can interfere with behaviour by inducing an increase in average pause length during locomotion, and show that this increase in pausing requires both str-217 and ADL neurons. Finally, we demonstrated that ADL neurons are activated by DEET and that optogenetic activation of ADL neurons increased average pause length. This is consistent with the 'confusant' hypothesis, which proposes that DEET is not a simple repellent but that it instead modulates multiple olfactory pathways to scramble behavioural responses(10,11). Our results suggest a consistent motif in the effectiveness of DEET across widely divergent taxa: an effect on multiple chemosensory neurons that disrupts the pairing between odorant stimulus and behavioural response.

机译：DEET（N，N-二乙基-间甲酰胺）是美国农业部于1946年鉴定的一种合成化学药品，用于筛选驱蚊剂以保护士兵免受蚊子传播的疾病（1,2）。自发现以来，DEET已成为世界上使用最广泛的节肢动物驱避剂，并有效地对抗了经过数百万年进化而分离的无脊椎动物，包括叮咬的苍蝇（3），蜜蜂（4），壁虱（5）和陆地水ches（3）。。在昆虫中，DEET作用于嗅觉系统（5-12），并需要嗅觉受体共受体Orco（7,9-12），但确切的工作方式仍存在争议（13）。在这里，我们显示线虫秀丽隐杆线虫对DEET敏感，并使用这种遗传上易处理的动物来研究这种化学物质的作用机理。我们发现，DEET不是挥发性的驱避剂，而是选择性地干扰了对各种引诱剂和驱避剂分子的趋化性。在对DEET抗性蠕虫的正向遗传筛选中，我们鉴定了一个编码单个G蛋白偶联受体str-217的基因，该基因在对DEET有反应的一对化学感应神经元中被称为ADL神经元。在另一个化学感觉神经元中str-217的错误表达赋予了对DEET的反应。工程改造的str-217突变体以及带有str-217缺失的秀丽隐杆线虫野生分离株对DEET具有抗性。我们发现DEET可以通过在运动过程中引起平均停顿长度的增加来干扰行为，并表明这种暂停的增加需要str-217和ADL神经元。最后，我们证明了DEDL激活了ADL神经元，而ADL神经元的光遗传学激活增加了平均停顿长度。这与``令人困惑''的假设一致，后者提出DEET不是简单的驱避剂，而是通过调节多种嗅觉途径来扰乱行为反应（10,11）。我们的结果表明，在广泛不同的类群中，DEET的有效性具有一致的基序：对多个化学感觉神经元的影响，破坏了气味刺激与行为反应之间的配对。

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来源
《Nature》 |2018年第7725期|119-123|共5页
作者
Dennis Emily J.; Dobosiewicz May; Jin Xin; Duvall Laura B.; Hartman Philip S.; Bargmann Cornelia I; Vosshall Leslie B.;
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作者单位

Rockefeller Univ, Lab Neurogenet & Behav, 1230 York Ave, New York, NY 10021 USA;

Rockefeller Univ, Lulu & Anthony Wang Lab Neural Circuits & Behav, New York, NY 10021 USA;

Rockefeller Univ, Lulu & Anthony Wang Lab Neural Circuits & Behav, New York, NY 10021 USA;

Rockefeller Univ, Lab Neurogenet & Behav, 1230 York Ave, New York, NY 10021 USA;

Texas Christian Univ, Dept Biol, Ft Worth, TX 76129 USA;

Rockefeller Univ, Lulu & Anthony Wang Lab Neural Circuits & Behav, New York, NY 10021 USA;

Rockefeller Univ, Lab Neurogenet & Behav, 1230 York Ave, New York, NY 10021 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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A natural variant and engineered mutation in a GPCR promote DEET resistance in C. elegans

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