Abstract
In mice, trace amine-associated receptors (TAARs) are interspersed in the olfactory epithelium and constitute a chemosensory subsystem that is highly specific for detecting volatile amines. Humans possess six putative functional TAAR genes. Human TAAR5 (hTAAR5) is highly expressed in the olfactory mucosa and was shown to be specifically activated by trimethylamine. In this study, we were challenged to uncover an effective blocker substance for trimethylamine-induced hTAAR5 activation. To monitor blocking effects, we recombinantly expressed hTAAR5 and employed a commonly used Cre-luciferase reporter gene assay. Among all tested potential blocker substances, Timberol®, an amber-woody fragrance, is able to inhibit the trimethylamine-induced hTAAR5 activation up to 96%. Moreover, human psychophysical data showed that the presence of Timberol® increases the olfactory detection threshold for the characteristic fishy odor of trimethylamine by almost one order of magnitude. In conclusion, our results show that among tested receptors Timberol® is a specific and potent antagonist for the hTAAR5-mediated response to trimethylamine in a heterologous system. Furthermore, our data concerning the observed shift of the olfactory detection threshold in vivo implicate that hTAAR5 or other receptors that may be inhibited by Timberol® could be involved in the high affinity olfactory perception of trimethylamine in humans.
Highlights
Trimethylamine (TMA) is an organic compound with a characteristic fishy odor
Human TAAR5-transfected HANA3A cells were stimulated with a mix of the agonist TMA (300 μM) and 100 μM of a potential blocker substance (Fig 1)
Subsequent screening with 18 non-related chemical structures revealed that 100 μM Timberol1 was able to inhibit Human TAAR5 (hTAAR5) responses to 300 μM TMA by 72% ± 6%
Summary
Trimethylamine (TMA) is an organic compound with a characteristic fishy odor. The tertiary amine arises by choline metabolism from precursors in food digestion and is decomposed into odorless trimethylamine oxide by the liver enzyme flavin monooxygenase (FMO3). Elevated TMA levels occurring in human urine, sweat or breath are thought to be caused by reduced FMO3 production or altered FMO3 function, resulting in fish odor syndrome or trimethylaminuria [1,2,3]. The FMO3 metabolic capacity is altered during menstrual periods or pregnancy, which suggests that sex hormones might play a role [4,5,6]. PLOS ONE | DOI:10.1371/journal.pone.0144704 December 18, 2015
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