Grapefruit-derived nootkatone potentiates GABAergic signaling and acts as a dual-action mosquito repellent and insecticide

Humanity has long battled mosquitoes and the diseases they transmit—a struggle intensified by climate change and globalization, which have expanded mosquito ranges and the spread of associated diseases.1 Additionally, widespread insecticide resistance has reduced the efficacy of current control methods, necessitating new solutions.2,3 Nootkatone, a natural compound found in grapefruit, shows promise as both a mosquito repellent and an insecticide.4,5 However, its mechanism of action remains unclear. Our study demonstrates that nootkatone acts as a potent spatial and contact repellent against multiple mosquito species. Nootkatone-induced spatial aversion, which is influenced by human odor, is in Aedes aegypti partially mediated by Orco- and ionotropic receptor (IR)-positive neurons, while contact aversion is robust and likely mediated via the proboscis and independent of TRPA1 and IRs. We further find that nootkatone potentiates γ-aminobutyric acid (GABA)-mediated signaling by modulating the broadly expressed major insect GABA-gated chloride channel resistant to dieldrin (Rdl). At low doses, the chemosensory-mediated spatial and contact repellency is likely strengthened by nootkatone’s disruption of synaptic transmission in select mosquito sensory neurons. At higher doses, nootkatone induces paralysis and death, presumably through broad-range synaptic transmission disruption. These findings reveal nootkatone’s unique mode of action and highlight its potential as an effective mosquito control agent. Its dual role as a repellent and an insecticide, combined with low-to-no toxicity to humans and a pleasant smell, underscores nootkatone’s promise as a future tool in mosquito control efforts. [Display omitted] •Nootkatone, found in grapefruit, acts as both a repellent and an insecticide•Spatial aversion in Aedes aegypti involves Orco and ionotropic receptor neurons•The proboscis senses nootkatone for contact repellency, independent of TRPA1 and IRs•Nootkatone modulates Rdl channels, potentiating GABA inhibition in mosquitoes Triana and Andreazza et al. describe nootkatone, a grapefruit volatile, as a potent mosquito repellent and an insecticide. Nootkatone induces spatial and contact repellency, preventing feeding, and potentiates GABA-mediated inhibition, causing paralysis. Its safety for humans and pleasant scent makes nootkatone a promising option for mosquito control.