Identification of new agonists and antagonists of the insect odorant receptor co-receptor subunit.
Identification of new agonists and antagonists of the insect odorant receptor co-receptor subunit.
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DOI：
10.1371/journal.pone.0036784
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Luetje CW
中科院分区：
文献类型：
--
作者：
Chen S;Luetje CW
昆虫使用几个化学感受器家族（包括嗅觉受体的OR家族）来检测有吸引力和厌恶性的化学物质，使得这些受体成为控制昆虫的吸引人的靶标。昆虫的气味受体是气味门控离子通道，由至少一个共同亚基（气味受体辅助受体亚基，Orco）和至少一个可变的气味特异性亚基组成。昆虫物种的许多OR中的每一个都被一组独特的气味剂激活或抑制，所述气味剂与可变的气味剂特异性亚基相互作用，使得OR导向的昆虫控制剂的开发复杂且费力。然而，几种N-，2-取代的三唑硫代乙酰胺化合物（VUAA 1，VU 0450667和VU 0183254）最近显示直接作用于高度保守的Orco亚基，这表明可以开发具有广泛活性的化合物。我们已经探索了VUAA 1结构周围的化学空间，以确定新的Orco配体。我们从几种昆虫物种中筛选OR，使用爪蟾卵母细胞中的异源表达和电生理测定，与VUAA 1结构相关的22种化合物的面板。通过改变吡啶环上的氮原子位置和苯环上的修饰基团，我们鉴定了两种新的激动剂和一系列竞争性拮抗剂。筛选较小的化合物，类似于VUAA 1结构的部分，也产生了竞争性拮抗剂。重要的是，我们表明，Orco拮抗剂抑制气味激活的OR从几种昆虫物种。对一种拮抗剂的详细检查证明抑制是通过非竞争性机制进行的。来自不同物种的Orco亚基显示的激动剂和拮抗剂敏感性的类似模式表明高度保守的结合位点结构。通过Orco拮抗作用抑制气味剂活化的易感性在不同的昆虫物种中是保守的，这使得Orco上的配体结合位点成为开发新型的、广泛活性的昆虫驱避剂的有希望的靶标。
Insects detect attractive and aversive chemicals using several families of chemosensory receptors, including the OR family of olfactory receptors, making these receptors appealing targets for the control of insects. Insect ORs are odorant-gated ion channels, comprised of at least one common subunit (the odorant receptor co-receptor subunit, Orco) and at least one variable odorant specificity subunit. Each of the many ORs of an insect species is activated or inhibited by an unique set of odorants that interact with the variable odorant specificity subunits, making the development of OR directed insect control agents complex and laborious. However, several N-,2-substituted triazolothioacetamide compounds (VUAA1, VU0450667 and VU0183254) were recently shown to act directly on the highly conserved Orco subunit, suggesting that broadly active compounds can be developed. We have explored the chemical space around the VUAA1 structure in order to identify new Orco ligands. We screened ORs from several insect species, using heterologous expression in Xenopus oocytes and an electrophysiological assay, with a panel of 22 compounds structurally related to VUAA1. By varying the nitrogen position in the pyridine ring and altering the moieties decorating the phenyl ring, we identified two new agonists and a series of competitive antagonists. Screening smaller compounds, similar to portions of the VUAA1 structure, also yielded competitive antagonists. Importantly, we show that Orco antagonists inhibit odorant activation of ORs from several insect species. Detailed examination of one antagonist demonstrated inhibition to be through a non-competitive mechanism. A similar pattern of agonist and antagonist sensitivity displayed by Orco subunits from different species suggests a highly conserved binding site structure. The susceptibility to inhibition of odorant activation by Orco antagonism is conserved across disparate insect species, suggesing the ligand binding site on Orco as a promising target for the development of novel, broadly active insect repellants.
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