The ability to modulate sensitivity in sensory systems is essential for useful information to be extracted from fluctuating stimuli in a wide range of background conditions. The mechanisms underlying sensitivity regulation in insect primary olfactory neurons are poorly understood. Here we reveal that dephosphorylation of OrcoS289 that occurs upon prolonged odor exposure is a mechanism underlying reduction in odorant sensitivity in Drosophila primary olfactory neurons in both sexes. OrcoS289A mutants, unable to phosphorylate this position, have low intrinsic odorant sensitivity that is independent of altered expression or localization. A phosphomimetic allele, OrcoS289D, has enhanced odorant sensitivity compared with wild-type controls. To explore the functional ramifications of this phosphorylation in vivo, we generated phospho-specific antiserum to OrcoS289 and show that phosphorylation at this residue is dynamically regulated by odorant exposure with concomitant modulation of odorant sensitivity. OrcoS289 is phosphorylated in the sensitized state, and odorant exposure triggers dephosphorylation and desensitization without altering receptor localization. We further show that dephosphorylation of OrcoS289 is triggered by neuronal activity, and not conformational changes in the receptor occurring upon ligand binding. Mutant flies unable to regulate Orco function through phosphorylation atS289 are defective for odor-guided behavior. These findings provide insight into the mechanisms underlying regulation of insect odorant receptors in vivo.
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