title: Positive Allosteric Modulation of Insect Olfactory Receptor Function by ORco Agonists.
abstract: Insect olfactory receptors (ORs) are heteromeric ligand-gated cation channels composed of a common olfactory receptor subunit (ORco) and a variable subunit (ORx) of as yet unknown structures and undetermined stoichiometries. In this study, we examined the allosteric modulation exerted onAnopheles gambiaeheteromeric ORx/ORco olfactory receptorsin vitroby a specific class of ORco agonists (OAs) comprising ORcoRAM2 and VUAA1. High OA concentrations produced stronger functional responses in cells expressing heteromeric receptor channels relative to cells expressing ORco alone. These OA-induced responses of ORx/ORco channels were also notably much stronger than those obtained upon administration of ORx-specific ligands to the same receptors. Most importantly, small concentrations of OAs were found to act as strong potentiators of ORx/ORco function, increasing dramatically both the efficacy and potency of ORx-specific odorants. These results suggest that insect heteromeric ORs are highly dynamic complexes adopting different conformations that change in a concerted fashion as a result of the interplay between the subunits of the oligomeric assemblies, and that allosteric modulation may constitute an important element in the modulation and fining tuning of olfactory reception function.
authors.affiliation: Insect Molecular Genetics and Biotechnology Group, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos" Athens, Greece.
authors.forename: Panagiota
authors.initials: P
authors.lastname: Tsitoura
authors.affiliation: Insect Molecular Genetics and Biotechnology Group, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos" Athens, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Iatrou
keywords: Anopheles gambiae; ORco agonists; cell-based screening; ligand discovery; malaria; mosquito olfaction; olfactory function enhancement; olfactory receptor pharmacology