Odorant Receptor Inhibition is Fundamental to Odor Encoding
2019
Most natural odors are complex mixtures of many volatile components, competing to bind
odorant receptors (ORs) expressed in olfactory sensory neurons (OSNs) of the nose. To date
surprisingly little is known about how OR antagonism shapes neuronal representations in the
periphery of the olfactory system. Here, we investigated its prevalence, the degree to which it
disrupts OR ensemble activity, and its conservation across related ORs. Calcium imaging
microscopy of dissociated OSNs revealed significant inhibition, often complete attenuation, of
responses to indole, a commonly occurring volatile associated with both floral and fecal odors,
by a set of 36 tested odorants. To confirm an OR mechanism for the observed inhibition, we
performed single-cell transcriptomics on OSNs that exhibited specific response profiles to a
diagnostic panel of odorants and identified the receptor Olfr743 which, when tested in vitro,
recapitulated ex vivo responses. We screened ten ORs from the Olfr743 clade with 800
perfumery-related odorants spanning a range of chemical scaffolds and functional groups, over
half of which (430) antagonized at least one of the ten ORs. Furthermore, OR activity outcomes
were divergent rather than redundant, even for the most closely related paralogs. OR activity
fitted a mathematical model of competitive receptor binding and suggests that normalization of
OSN ensemble responses to odorant mixtures is the rule rather than the exception. In summary,
we observed OR antagonism, inverse agonism and partial agonism occurring frequently and in
a combinatorial manner. Thus, extensive receptor-mediated computation of mixture information
appears to occur in the olfactory epithelium prior to transmission of odor information to the
olfactory bulb.
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