Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 296, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1074/jbc.RA120.016557
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Funding
- European Cooperation in Science and Technology (COST) Action [CA18133]
- OPENSCREEN-GR (An Open-Access Research Infrastructure of Chemical Biology and Target-Based Screening Technologies for Human and Animal Health, Agriculture and the Environment) - Operational Program Competitiveness, Entrepreneurship and Innovation (NSRF [MIS 5002691]
- European Union (European Regional Development Fund)
- Israel Science Foundation [1990/16]
- project LIFE CONOPS of the program LIFE + Environment Policy and Governance - European Commission [LIFE12 ENV/GR/000466]
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Insects' odor-dependent behaviors are triggered by the binding of odorant ligands to olfactory receptors, and specific odor binding to the common subunit of odorant receptor heteromers can affect olfactory receptor function and behavioral responses. Antagonists of the odorant receptor coreceptor were identified in natural volatile organic compounds, which inhibited the function of certain mosquito species' olfactory receptors and repelled them. Mixtures of these antagonists showed enhanced repellency, indicating additive effects on olfactory receptor function rather than synergy.
Odorant-dependent behaviors in insects are triggered by the binding of odorant ligands to the variable subunits of heteromeric olfactory receptors. Previous studies have shown, however, that specific odor binding to ORco, the common subunit of odorant receptor heteromers, may allosterically alter olfactory receptor function and profoundly affect subsequent behavioral responses. Using an insect cell-based screening platform, we identified and characterized several antagonists of the odorant receptor coreceptor of the African malaria vector Anopheles gambiae (AgamORco) in a small collection of natural volatile organic compounds. Because some of the identified antagonists were previously shown to strongly repel Anopheles and Culex mosquitoes, we examined the bioactivities of the identified antagonists against Aedes, the third major genus of the Culicidae family. The tested antagonists inhibited the function of Ae. aegypti ORco ex vivo and repelled adult Asian tiger mosquitoes (Ae. albopictus). Binary mixtures of specific antagonists elicited higher repellency than single antagonists, and binding competition assays suggested that this enhanced repellence is due to antagonist interaction with distinct ORco sites. Our results also suggest that the enhanced mosquito repellency by antagonist mixtures is due to additive rather than synergistic effects of the specific antagonist combinations on ORco function. Taken together, these findings provide novel insights concerning the molecular aspects of odorant receptor function. Moreover, our results demonstrate that a simple screening assay may be used for the identification of allosteric modifiers of olfactory-driven behaviors capable of providing enhanced personal protection against multiple mosquito-borne infectious diseases.
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