Submitted to: Neuropharmacology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 1/9/2012
Publication Date: 4/1/2012
Citation: Bohbot, J.D., Dickens, J.C. 2012. Odorant receptor modulation: Ternary paradigm for mode of action of insect repellents. Neuropharmacology. 62:2086-2095. Interpretive Summary: Mosquitoes vector numerous diseases including malaria, dengue, Yellow fever and West Nile virus, which are responsible for substantial human suffering and more than one million deaths each year world-wide. One way to decrease the ability of mosquitoes to transmit disease is the use of chemical repellents such as DEET to minimize contact between mosquitoes and their human or animal hosts. While repellents are often considered to exert their effects on odor receiving proteins in mosquitoes, thus interfering with their behavior, the ways they do this are not well understood. Now we show that repellents interact with odor receiving proteins in at least three ways: direct stimulation of the odor receiving receptor, blockage of the odor receptor, or changing the response of the odor receptor to an attractant. This information will be used by chemists and pharmacologists to direct development of novel mosquito repellents for protection of humans and animals.
Technical Abstract: The modulation of insect behavior for the purpose of controlling the spread of infectious diseases has been the task of a few insect repellents for which the mechanistic modes of action on odorant receptors (ORs) are unclear. Here, we study the effects of the repellents DEET and IR3535, and a novel OR co-receptor (Orco) agonist on odorant-evoked currents in Xenopus oocytes expressing two subtypes of Aedes aegypti ORs (Aaeg\ORs). We show that DEET and IR3535 behave as insurmountable antagonists of ORs, and that modulation of OR activity is not restricted to antagonism and agonism, but also includes synergism. This knowledge of the molecular mechanisms underlying OR blockade, activation and hyperactivation will be fundamental to the development of novel strategies for the control of mosquito behavior.