Nature, published online 21 September 2011, doi:10.1038/nature10438

The mechanism by which the insect repellant N,N-diethyl-meta-toluamide (DEET) functions remains unclear, but possibilities include interference with the olfactory system to block odor recognition or activation of olfaction to elicit avoidance. To distinguish between these models, Pellegrino et al. tested the effects of DEET on the electrophysiological responses of four Drosophila melanogaster olfactory sensory neurons (OSNs) to ten attractive odors. Different OSNs express distinct odorant receptors (ORs) that consist of a common coreceptor, Orco, and variable OR subunits that confer odor selectivity. Depending on the OSN, DEET either suppressed odor-mediated inhibition or decreased odor-induced activation. Interestingly, the odors 1-octen-3-ol and 1-octanol had opposing effects on neurons of the same olfactory hair: they inhibited the neuron expressing Or59b as the variable OR subunit and activated the one expressing Or85a. DEET inverted these responses, leading the authors to hypothesize that DEET acts as a molecular 'confusant' by scrambling the odor code via direct modulation of ORs. Further study of the Or59b–Orco complex suggested two odor-binding sites: a high-affinity site modulated by DEET and a low-affinity site insensitive to DEET. Finally, they found a D. melanogaster strain harboring a mutation that renders Or59b insensitive to inhibition by odor ligands and modulation by DEET, providing further evidence that DEET functions by directly interacting with ORs and alters fine-tuning of the insect olfactory system.