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.