Author
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Bohbot, Jonathan |
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Dickens, Joseph |
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Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 7/21/2010 Publication Date: 8/11/2010 Citation: Bohbot, J.D., Dickens, J.C. 2010. Insect Repellents: Modulators of mosquito odorant receptor activity. PLoS One. 5(8):e12138. Interpretive Summary: Diseases vectored by mosquitoes kill between 1 million and 3 million people annually worldwide. Chemical repellents are one means of preventing contact by these dangerous insect vectors with their human or animal hosts thereby reducing disease transmission. However, the mechanisms by which repellents have their effects have been poorly understood. Here we show, at the molecular level, that commonly used insect repellents differentially affect specific odor receptors in the yellow fever mosquito which negate its ability to detect chemical attractants produced by humans or animals. These results provide a better understanding of the mode of action of insect repellents and will be used by chemists and pharmacologists as the basis for discovery of novel or enhanced repellents, or combinations of repellents based on their differential effects on specific odor receptors. Technical Abstract: Mosquitoes vector numerous pathogens that cause diseases including malaria, yellow fever, dengue fever and chikungunya. DEET, IR3535, Picaridin and 2-undecanone are insect repellents that are used to prevent interactions between humans and a broad array of disease vectors including mosquitoes. While the effectiveness of these compounds has been proven at the behavioral and physiological levels, it is only recently that understanding their molecular mode of action has become an active topic. DEET, in particular, has been shown to target molecular components of the olfactory and cholinergic pathways. Here, we have used the two-electrode voltage clamping of expressed Ae. aegypti odorant receptors (AaOrs) — AaOR2 with its cognate ligand indole and AaOR8 with its ligand (R)-(-)-1-octen-3-ol — in Xenopus oocytes to investigate the potential inhibitory activities of these known repellents. We show that both the ligand-activated subunits AaOR2 and AaOR8, as well as their obligatory partner AaOR7, are differentially targeted by these chemicals. The sequence diversity between these 2 mosquito ORs, the exquisite ligand selectivity of AaOR8, and the data presented here provide compelling evidence that OR assemblages harbor allosteric sites that are targeted by small repellent molecules. Considering our current report and previous studies, it is likely that repellents affect arthropod behaviors via widely different targets and modes of action. |
