SPLTRAK Abstract Submission
Specific Antagonism is Prominent in Odorant Receptor-Based Combinatorial Coding
Patrick Pfister, Barry J. Evans, Casey Trimmer, Randy Arroyave, Mushhood Sheikh, Matthew E. Rogers
Firmenich Incorporated, Corporate Research and Development, Plainsboro, NJ, United States

Little is known about the role of odorant receptor (OR) antagonism in shaping the combinatorial code upon complex odor presentation. Here, we sought to investigate antagonism and its pharmacology using an in vitro high-throughput screening platform.  We first deorphaned the mouse receptor Olfr743 through single-cell transcriptomics of indole- and skatole-activated olfactory sensory neurons (OSNs). Subsequent phylogenetic analyses revealed the existence of six paralogous receptors sharing over 78% amino acid identity and an additional six members of the closest outgroup ranging over 56% identity. We first characterized the in vitro response profile of these ORs with chemical indole analogs and revealed partially-overlapping but distinct agonist activation profiles. We then used a set of 800 chemically diverse perfumery ingredients to probe the inhibition profiles of a subset of 10 indole-responsive ORs (including all Olfr743 paralogs) in the presence of indole and observed distinct receptor-specific inhibition profiles. 422 compounds antagonized the activity of at least one OR. We found the number of antagonists and the overlap in antagonists varied widely among ORs; furthermore, in some cases, a compound acted as an activator for one OR and an antagonist for another. Such distinct activation and inhibition profiles between paralogous genes supports the view that OR gene diversification leads to receptive range diversification rather than functional redundancy for both agonism and antagonism. Taken together, we conclude that, even within a family of closely related receptors, antagonism is widespread, likely to play a prominent role in olfactory peripheral computation and may serve to expand the encoding capacity of the system.