Dual Activities of Odorants on Olfactory and Nuclear Hormone Receptors

Abstract

We have screened an odorant compound library and discovered molecules acting as chemical signals that specifically activate both G-protein-coupled olfactory receptors (ORs) on the cell surface of olfactory sensory neurons and the human nuclear estrogen receptor ␣ (ER) involved in transcriptional regulation of cellular differentiation and proliferation in a wide variety of tissues. Hence, these apparent dual active odorants induce distinct signal transduction pathways at different subcellular localizations, which affect both neuronal signaling, resulting in odor perception, and the ER-dependent transcriptional control of specific genes. We demonstrate these effects using fluorescence-based in vitro and cellular assays. Among these odorants, we have identified synthetic sandalwood compounds, an important class of molecules used in the fragrance industry. For one estrogenic odorant we have also identified the cognate OR. This prompted us to compare basic molecular recognition principles of odorants on the two structurally and apparent functionally non-related receptors using computational modeling in combination with functional assays. Faced with the increasing evidence that ORs may perform chemosensory functions in a number of tissues outside of the nasal olfactory epithelium, the unraveling of these molecular ligand-receptor interaction principles is of critical importance. In addition the evidence that certain olfactory sensory neurons naturally co-express ORs and ERs may provide a direct functional link between the olfactory and hormonal systems in humans. Our results are therefore useful for defining the structural and functional characteristics of ER-specific odorants and the role of odorant molecules in cellular processes other than olfaction.Our nose detects a large variety of odorant signals relying on about 350 different predicted G-protein-coupled olfactory receptors (ORs) 3 with a conserved seven-transmembrane helical structure (1-3). By binding odorant molecules ORs modulate the conversion of chemical into electrical neuronal signals that are finally decoded in higher brain regions to trigger emotional and behavioral responses (4 -6). Odorants are generally small, hydrophobic organic molecules with highly variable chemical structures and properties (7). They easily pass cell membranes, and, due to their enormous chemical diversity, some of them might, apart from their "conventional" role in olfaction, trigger also yet unknown cellular processes. The role of specific ORs in sperm chemotaxis has been documented (8,9), and the widespread ectopic expression of OR genes in a large number of non-olfactory human tissues implicates additional, unproven functions of ORs in embryonic development and cell-cell recognition (10), and proliferation rates in prostate cancer cells (11). Recent findings indicate that ORs might also have chemosensory functions in kidney (12). Although most present efforts concentrate on matching odorants with their cognate ORs to define their molecular receptive ranges and receptor fu...

Monitoring proliferative activities of hormone-like odorants in human breast cancer cells by gene transcription profiling and electrical impedance spectroscopy

“…A recent study showed up-regulation of a single marker gene by benzylphenylmethylpropional (Lilial, commercially used in perfumes) in MCF7 cells at concentrations similar to those used in our present study (Charles and Darbre 2009;Pick et al, 2009), We provide here initial evidence for extended regulatory activities of synthetic odorants on a set of ERα-dependent genes suggesting potentially broad influences of these compounds on cellular processes. While we have shown that sandalwood odorants modify gene transcription rapidly, reaching amplitudes comparable to those elicited by E2, significantly lower effects were reported for Lilial.…”

“…The EC50 values of the different compounds obtained from ECIS compare well with data obtained from different biochemical tests (Pick et al, 2009). According to the impedance responses the signatures of JV and PS are characteristic of full agonists of ERα.…”

“…For all of these substances, the estrogenic potency was low compared to E2 (Bitsch et al, 2002). Elsewhere, we have shown that sandalwood odorants substantially increased MCF7 proliferation to a similar extent as E2 but at elevated concentrations (Pick et al, 2009). This further underscores their role as ERα-specific agonists.…”

“…Some sandalwood odorants can have a profound effect on cell division in human breast cancer MCF7 cells (Pick et al, 2009). As proliferation of MCF7 cells is controlled by ERα-mediated gene (Fig.…”

“…We focused on estrogenic sandalwood odorants, which are widely-used in perfumes and fragranced body care products. Elsewhere, we demonstrated their proliferative effects in MCF7 cells mediated by ERα (Pick et al, 2009). Here, we investigated the effects of sandalwood odorants on the regulation of gene transcription and activation of cellular signaling pathways.…”