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Abstract
Olfaction is mediated by the binding of odorant molecules to olfactory receptors (ORs). There are numerous proteins in the nasal mucus, and they contribute to olfaction through various mechanisms. Cytochrome P450 (CYP) family members are known to be present in the olfactory epithelium and are thought to affect olfaction by enzymatic conversion of odorant molecules. In this study, we examined the effects of CYPs on the ligand responses of ORs in heterologous cells. Among the CYPs tested, co-expression of CYP1a2 significantly affected the responses of various ORs, including MOR161-2, to acetophenone. Conversion of acetophenone to methyl salicylate was observed in the medium of CYP1a2-expressing cells. MOR161-2-expressing cells exhibited significantly greater responses to methyl salicylate than to acetophenone. Finally, we analyzed the responses of olfactory neurons expressing MOR161-2 in vivo using the phosphorylated ribosomal protein S6 as a marker. MOR161-2 responded to both acetophenone and methyl salicylate in vivo. When the olfactory mucus was washed out by the injection of PBS to mouse nasal cavity, the response of MOR161-2 to acetophenone was reduced, while that to methyl salicylate did not change. Our data suggest that CYP1a2 affects OR activation by converting acetophenone to methyl salicylate.
Highlights
Olfaction is mediated by olfactory receptors (ORs) expressed on the cilia of olfactory sensory neurons (OSNs), which are located in the olfactory epithelium (OE)[1]
We could not obtain the solid evidence for the effect of cytochrome P450 (CYP) on olfaction in vivo, these results indicate that some factors in the nasal mucus are responsible for the enhancement of MOR161-2 response to acetophenone
The olfactory epithelium expresses various metabolic enzymes, such as cytochrome P450, dehydrogenases, oxidases, reductases, and esterases, which degrade various chemicals coming from the outside world[20,21,22,23,24]
Summary
Olfaction is mediated by olfactory receptors (ORs) expressed on the cilia of olfactory sensory neurons (OSNs), which are located in the olfactory epithelium (OE)[1]. By the co-expression of these proteins, various ORs were functionally expressed, and their ligands were determined It has been found, that for some odorants, there are differences between the ligand specificity of an odorant receptor in vitro and the responsiveness of its corresponding glomerulus in vivo[9]. Quinoline and coumarin are metabolized by CYPs, whereas isoamyl acetate is hydrolyzed by carboxylesterases Metabolites of these chemicals elicited lower olfactory response amplitudes than their parent molecules. It is reasonable to think that the enzymatic activity of CYPs expressed in OE metabolizes odorants that are dissolved in olfactory mucus and that CYP activity influences the differences in OR activities in response to odorants between in vivo and in vitro contexts. Nagashima et al reported an increase in the response of ORs, suggesting that the metabolite might induce a stronger response of ORs than the original odorant[11]
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