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Humans have about 400 odorant receptors (ORs), but scientists have had trouble finding ligands that match up with most of these ORs in lab settings—leaving them with a murky understanding of how certain smells are recognized in our brains. Only 71 human receptor-ligand interactions have been identified in studies thus far, often with low sensitivity in assays. Scientists have struggled with poor in vitro expression of ORs in lab conditions, limiting identification of receptor–odorant pairs.

In 2004, the field of olfactory science appeared to gain some progress in the form of a Nobel-winning hypothesis called the "combinatorial model," which suggested that multiple ORs contribute to the perception of a single odorant. However, a new study, recently in Current Biology, paints a somewhat different picture.

For their study, a group of Swiss researchers tweaked the C-terminal domains of ORs, which resulted in dramatically boosted OR cell-surface expression and sensitivity in lab conditions. This allowed the group to test out which ORs respond to various scents, like ambergris, rose, vanilla, and corked wine. Using this method, they were able to "de-orphanize" several ORs, or find matching ligands for them, resulting in novel OR identification for odorants.

Interestingly, the method significantly increased sensitivity. The prior 71 human receptor–ligand interactions had sensitivities far lower than those in the new data.

"In a recent review of all published human OR activation data, a median EC50 of 10^−4 M was reported. For all the ORs investigated in this study, the median is 1.6 × 10^−6 M, confirming the approximately 100-fold improvement in sensitivity of the assay for de-orphanized ORs," the study authors explain.

While some odorants may still require multiple ORs for perception, the results here also indicated that single ORs can dominate the perception of certain signature odorants. This specificity with which some of the ORs were identified was particularly intriguing, hinting that the combinatorial model may not be universal, at the very least.

The study authors write, "It is noteworthy that we identified highly specific ORs, which appear to be responsible for specific odor descriptors or percepts linked to complex groups of odorants. Thus, OR2M2, OR2A25, and OR10G3 each bind to chemically divergent structures, but sharing the same 'grapefruit' or 'rosy' or 'vanilla' odor description, and they add to the example of OR5A2, a single OR detecting diverse structures with the common 'musky' description."

In some cases, they found that odorants, like Arborone, could be sufficiently detected with one OR, despite previous studies indicating that it would bind to at least 10.

They say, "Our data for (±)-Arborone show preferential binding to OR7A17, and the high potency and correlation of in vivo sensitivity and OR7A17 activation by woody odorants in general align with a model whereby OR7A17 activation suffices for a woody perception.

"Likewise, the data for the other 21 ORs characterized in detail now indicate that human olfaction, at least for signature odorants with a distinct percept, is far more pharmacological, i.e., with a specific ligand binding to a major target OR, which, on its own, recognizes the confined structure of the ligand, thereby triggering the sensation of a specific odor direction."

Still, the group does note that further optimization of the method is needed, as it may enable expression of more ORs and in vitro sensitivity may still not fully match in vivo human olfaction. A better understanding of OR–ligand pairing may eventually result in improvements in technologies involving things like the detection of food spoilage or environmental contaminants.

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