Insect repellents exert their effects through interactions with
ORs and GRs in mosquitoes. The fact that DEET modulates responses
of ORs ex vivo in Ae. aegypti [13] is supported by studies
in Drosophila where DEET was shown to alter responses of ORNs
to their ligands based on the concentration of the odor [10]. In
addition, DEET, IR3535, Picaridin, and citronellal stimulate a specific
GRN sensitive to feeding deterrents in Ae. aegypti [37].
How do DEET and other insect repellents interact with a multiplicity
of transmembrane proteins engaged in various sensory
modalities? It appears that part of the answer lies with the ability
of these compounds to interact with secondary recognition sites
(allosteric sites) on receptor proteins. It is also important to note
that these effects are observed when using high quantities of insect
repellents. These characteristics may explain how DEET affects the
behavior of diverse groups of arthropods. However, the receptor
specific effects of some repellents indicate that these compounds
have structural qualities that enable interactions with a variety
of molecular targets. This question will be best tested by looking
at the molecular mode of action of DEET on non-insect arthropods
such as ticks.
Pioneering independent studies had led to distinct theories on
the molecular mode of action of DEET in olfaction: (i) DEET alone
activates ORx-Orco in the absence of odorant or (ii) that DEET
inhibits the activation of ORx-Orco by the cognate ligand. We have
shown that both theories are not exclusive and depend on the ORx-
Orco construct and ligand contexts (presence or absence of cognate
ligands).
Understanding the mode of action of insect repellents and how
these chemicals interact with odorants to modulate OR and GR
activity will allow us to design potent formulations aimed at interfering
with insect sensory signaling to ultimately disrupt their cognitive
processes. It is also important to underscore the need to
understand the chemical ecology of mosquitoes and other targeted
pests in order to provide candidate semiochemicals necessary to
develop better attractants and repellent formulations. Identification
of new synthetic repellents or compounds with novel modes
of action will be facilitated by heterologous expression of targeted
ORs and GRs for discovery of allosteric recognition sites.