Dual activities of odorants on olfactory and nuclear hormone receptors.
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 alpha (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.
Pick
Horst
H
Institut des Sciences et Ingénierie Chimique, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Etter
Sylvain
S
Baud
Olivia
O
Schmauder
Ralf
R
Bordoli
Lorenza
L
Schwede
Torsten
T
Vogel
Horst
H
D004353:Drug Evaluation, Preclinical; D047628:Estrogen Receptor alpha / Q000032:analysis* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D009812:Odorants; D018034:Olfactory Receptor Neurons / Q000737:chemistry*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D018035:Receptors, Odorant / Q000032:analysis / Q000378:metabolism*; D032123:Santalum / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D012903:Smell; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D047628:Estrogen Receptor alpha; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D018035:Receptors, Odorant; D054852:Small Molecule Libraries