Odorants have the potential to enhance the heterologous expression of human olfactory receptors: Evidence from ethyl 3-phenylglycidate and its effects on OR1A1, OR11G2, and OR2W1

Abstract

Human olfactory receptors are G protein-coupled receptors that detect odorants and initiate olfactory signaling. Analyzing the olfactory receptor is important to elucidate the mechanism of olfaction. However, the expression of most human olfactory receptors in heterologous cell systems is challenging because of their poor stability and poor trafficking to the cell surface, which makes it difficult to analyze them. Here, we report a case in which an odorant enhanced the cell surface expression of human olfactory receptors. Using OR1A1 as a model olfactory receptor, we screened odorants and identified ethyl 3-phenylglycidate, which significantly increased both the total and cell surface expression levels of OR1A1 in a dose-dependent manner. This increase leads to an enhanced OR1A1 response to the agonist. Functional assays confirmed that ethyl 3-phenylglycidate acts as an agonist for OR1A1. Ethyl 3-phenylglycidate also enhances the expression of other human olfactory receptors, such as OR11G2 and OR2W1, which recognize ethyl 3-phenylglycidat as an agonist, like OR1A1. These findings indicate that ethyl 3-phenylglycidate stabilizes human olfactory receptors by binding to its ligand-binding pocket. Here, we showed the examples that treating human olfactory receptor-expressing cells with an odorant during the induction of hOR expression significantly increases the expression levels of the human olfactory receptor. Our findings provide a novel strategy to enhance the functional expression of human olfactory receptors, which will contribute to understanding of the functions of olfactory receptors as well as the mechanisms underlying olfactory perception.