Moon, M., Yun, J., Pyeon, M., Yun, J., Yang, J., Yeom, H.D., Lee, G., Choi, Y.S., Lee, J., Lee, J.H. (2025). Phenethyl Acetate as an Agonist of Insect Odorant Receptor Co-Receptor (Orco): Molecular Mechanisms and Functional Insights.  Int. J. Mol. Sci. 26(11): 4970.

FBrf0262644

Research paper

The insect olfactory system is vital for survival, enabling the recognition and discrimination of a wide range of odorants present in the environment. This process is mediated by odorant receptors (Ors) and the highly conserved co-receptor Orco. Insect Ors are structurally distinct from mammalian olfactory receptors, a divergence that presents unique advantages for developing insect-specific pest control strategies. In this study, we explored the molecular-level interactions between insect Ors and volatile organic compounds. Specifically, we investigated the response of Ors/Orco to phenethyl acetate (PA), a volatile compound found in the culture media of acetic acid bacteria. PA elicited activation in a concentration-dependent, reversible, and voltage-independent manner in Or1a, Or24a, and Or35a when combined with Orco, as well as in Orco homomers. Through molecular docking studies, we determined that the PA-binding site is localized to the Orco subunit, a highly conserved protein across diverse insect taxa. To further elucidate the role of key residues in the Orco homotetramer receptor, we performed site-directed mutagenesis. A mutational analysis identified W146 and E153 as critical residues for PA binding and activation. A double-mutant Orco receptor (W146A + E153A) exhibited a significant reduction in PA-induced activation compared to the wild-type receptor. These findings indicate that PA functions as an agonist for the Drosophila melanogaster Orco receptor and highlight its potential applications in chemosensory research and insect pest management strategies.

PMC12155335 (PMC) (EuropePMC)