Musk fragrance ingredients can have strikingly different molecular shapes. Yet we recognize them as members of a similar scent family, and a musk that one person struggles to detect may be noticeable to someone else in a tiny amount. Could the mechanisms that receive odor molecules in the nose explain both this common character and these individual differences?
In 2024, researchers at the fragrance company Givaudan studied three odorant receptors in cultured cells and compared their responses with differences in human genes and the amounts at which people first detected fragrance ingredients. Their aim was not simply to group musks under one scent, but to understand the mechanisms behind differences in perception from one ingredient to another.
Connecting cellular responses with the amount people first detect
Odorant receptors are proteins that transmit signals to cells in response to odor molecules. The three examined were OR5A2, OR5AN1, and OR1N2. The researchers added fragrance ingredients to cells expressing these receptors and measured responses as light signals. Because unmodified OR5A2 was difficult to express functionally in the experimental system, they used a version with a modified molecular terminus.
They first screened responses to 440 fragrance ingredients, then tested different concentrations. Separately, they examined the relationship between receptor responses and the smallest amounts people could detect for 50 macrocyclic lactone musks. Between four and eight assessors evaluated each ingredient in this test.
In the human tests, participants smelled ingredients emerging from a gas chromatograph through a dedicated sniffing port and pressed a button when they detected an odor. The amount was reduced stepwise, and the last amount detected at the correct time was recorded as the detection threshold. A smaller value means that someone can notice a smaller amount; it is not a rating of intensity at a fixed concentration or of preference.
Similar structures do not necessarily use the same receptor
OR5A2 responded to musks with a wide range of structures. Responses were observed not only to lactone, polycyclic, and linear musks but also to structurally different dienone musks. OR5AN1, meanwhile, responded strongly to certain macrocyclic ketones, including muscone, whereas OR1N2 responded to a more limited set of molecules, including ambrettolide.
Importantly, chemical classes and receptor roles did not have a one-to-one relationship. Ingredients within the same class could primarily activate different receptors, while structurally different ingredients could activate the same receptor. Some ingredients activated multiple receptors. This overlap matters when considering both what musks have in common and what distinguishes them.
Among the 50 lactones, ingredients that activated OR5A2 at lower concentrations tended to be detectable by people in smaller amounts. This provides a clue connecting cellular responses with human sensitivity. However, cultured cells and the nose differ in receptor abundance and their surrounding environment, so cellular measurements do not directly represent human sensation.
In 31 participants, differences appeared for some musks but not others
The researchers also genotyped the three receptors in 31 people and compared their detection thresholds for four musks. For the P172L variant, in which one amino acid in OR5A2 is substituted, 10 participants carried two reference copies, 15 carried one reference and one substituted copy, and six carried two substituted copies.
Participants with two substituted copies needed several tens of times more thibetolide and dihydroambrettolide to detect them than those with two reference copies. In the cell experiments, this OR5A2 variant was also less responsive to several musks. Differences in receptor function and human detection thresholds therefore pointed in the same direction.
For muscone and (E)-ambrettolide, however, no significant threshold difference by OR5A2 genotype was observed. The authors suggest that other receptors may support detection: OR5AN1 for muscone and OR1N2 for ambrettolide. The proposed compensatory role of OR1N2, in particular, is a hypothesis combining the cell responses and participant results. It was not tested by selectively disabling that receptor in the human nose.
Genetic associations alone cannot establish a receptor’s role
In this study, OR5AN1 genotype was also associated with detection thresholds for some lactones. Yet those lactones mainly activated OR5A2 in cells. Why would the gene for another receptor appear to be involved?
The two genes lie close together on a chromosome, and certain variants tend to be inherited together. As a result, a finding associated with one gene may actually reflect a functional difference in the other. The authors argue that combining human gene–perception associations with evidence about which receptors respond in cells is key to identifying their roles.
There are limitations, including the sample of 31 people and the use of a receptor modified for the experimental system. The human tests measured detection thresholds for a limited set of ingredients; they cannot fully explain the overall impression of a perfume, preferences, or how a fragrance changes over time. The study was funded entirely by Givaudan, and all authors were employees of the company. Data for some experimental musks were also subject to disclosure restrictions associated with patent applications.
Summary
This study connected the responses of three receptors with genetic differences to explain variation in musk sensitivity. OR5A2 responds to a broad range of musks, while OR5AN1 and OR1N2 contribute responses to other ingredients. Together, they help explain why someone may struggle to detect one musk yet still detect another.
The authors propose that these three receptors explain much of musk perception and that receptor responses could guide the design of new musks. The ability of macrocyclic musks to activate all three receptors offers a possible direction for fragrance development that also considers biodegradability. However, this study measured receptor responses and olfactory perception; it did not itself demonstrate the biodegradability or safety of new fragrance ingredients.
References
Emter, R., Merillat, C., Dossenbach, S., & Natsch, A.(2024). The trilogy of human musk receptors: linking receptor activation, genotype, and sensory perception. Chemical Senses, 49, bjae015. DOI: 10.1093/chemse/bjae015 / Full text.
© The Author(s) 2024. Published by Oxford University Press. All rights reserved. Publisher reuse terms.
