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Odorant Receptor Inhibition is Fundamental to Odor Encoding

54 Pages Posted: 6 Sep 2019 Sneak Peek Status: Review Complete

See all articles by Patrick Pfister

Patrick Pfister

Firmenich Inc.

Benjamin C. Smith

Firmenich Inc.

Barry J. Evans

Firmenich Inc.

Jessica H. Brann

Firmenich Inc.

Casey Trimmer

Firmenich Inc.

Mushhood Sheikh

Firmenich Inc.

Randy Arroyave

Firmenich Inc.

Gautam Reddy

University of California, San Diego (UCSD)

Hyo-Young Jeong

Firmenich Inc.

Daniel A. Raps

Firmenich Inc.

Zita Peterlin

Firmenich Inc.

Massimo Vergassola

University of California, San Diego (UCSD)

Matthew E. Rogers

Firmenich Inc.

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Abstract

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.

Keywords: olfaction, antagonism, G protein-coupled receptor, sensory coding, odor mixtures, olfactory receptor neurons

Suggested Citation

Pfister, Patrick and Smith, Benjamin C. and Evans, Barry J. and Brann, Jessica H. and Trimmer, Casey and Sheikh, Mushhood and Arroyave, Randy and Reddy, Gautam and Jeong, Hyo-Young and Raps, Daniel A. and Peterlin, Zita and Vergassola, Massimo and Rogers, Matthew E., Odorant Receptor Inhibition is Fundamental to Odor Encoding (September 4, 2019). CURRENT-BIOLOGY-D-19-01434. Available at SSRN: https://ssrn.com/abstract=3448157 or http://dx.doi.org/10.2139/ssrn.3448157
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Patrick Pfister

Firmenich Inc. ( email )

United States

Benjamin C. Smith

Firmenich Inc.

United States

Barry J. Evans

Firmenich Inc.

United States

Jessica H. Brann

Firmenich Inc.

United States

Casey Trimmer

Firmenich Inc.

United States

Mushhood Sheikh

Firmenich Inc.

United States

Randy Arroyave

Firmenich Inc.

United States

Gautam Reddy

University of California, San Diego (UCSD)

9500 Gilman Drive
Mail Code 0502
La Jolla, CA 92093-0112
United States

Hyo-Young Jeong

Firmenich Inc.

United States

Daniel A. Raps

Firmenich Inc.

United States

Zita Peterlin

Firmenich Inc.

United States

Massimo Vergassola

University of California, San Diego (UCSD)

9500 Gilman Drive
Mail Code 0502
La Jolla, CA 92093-0112
United States

Matthew E. Rogers (Contact Author)

Firmenich Inc. ( email )

United States

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