Functional Profiling of a Human Odorant Receptor Using Olfactory Cilia Links its Activation to Odor Quality
- 1Hunter College, CUNY
Abstract
The mechanism governing singular odorant receptor (OR) gene choice restricts each olfactory sensory neuron (OSN) to expressing a single OR allele from a repertoire of more than 1,100 receptor genes. Consequently, only a small fraction of OSNs express any given OR, limiting studies of OR function, axonal wiring, and odor coding. Here, we show that multimerizing a 21-bp homeodomain enhancer dramatically increases the probability of receptor choice. We engineered a single-copy Olfr151 minigene carrying a 9x21 enhancer and the human odorant receptor OR10G4, integrated at a genomic site distant from all endogenous OR clusters. This transgene drives singular OR10G4 expression in approximately 75% of OSNs and is accompanied by widespread reductions in endogenous Class I, Class II, and TAAR receptor transcripts and proteins, indicating that cis-regulatory elements govern the probability of OR selection. The abundance of OR10G4-expressing cilia enabled highly sensitive ligand screening using CELIA (Cilia-based Evaluation of Ligands and receptor InterActions). Profiling guaiacol derivatives revealed a strong correspondence among receptor activation, cAMP production, and published human psychophysical responses. Although OR10G4 responds to guaiacol-related odorants, multiple canonical vanilla odorants failed to activate the receptor, arguing against a primary role in vanilla perception. Instead, the lowest EC50 ligands were enriched for compounds human subjects described as smoky. Together, these findings link activation of a single human odorant receptor to a defined perceptual odor-quality dimension and establish a general strategy for decoding the molecular basis of human odor perception.
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BibTeX
@misc{lempert2026functional,
title = {{Functional Profiling of a Human Odorant Receptor Using Olfactory Cilia Links its Activation to Odor Quality}},
author = {E. Lempert and M. Omura and R. Mina and P. Feinstein},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753647},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753647v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Functional Profiling of a Human Odorant Receptor Using Olfactory Cilia Links its Activation to Odor Quality
AU - E. Lempert
AU - M. Omura
AU - R. Mina
AU - P. Feinstein
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753647
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753647v1
AB - The mechanism governing singular odorant receptor (OR) gene choice restricts each olfactory sensory neuron (OSN) to expressing a single OR allele from a repertoire of more than 1,100 receptor genes. Consequently, only a small fraction of OSNs express any given OR, limiting studies of OR function, axonal wiring, and odor coding. Here, we show that multimerizing a 21-bp homeodomain enhancer dramatically increases the probability of receptor choice. We engineered a single-copy Olfr151 minigene carrying a 9x21 enhancer and the human odorant receptor OR10G4, integrated at a genomic site distant from all endogenous OR clusters. This transgene drives singular OR10G4 expression in approximately 75% of OSNs and is accompanied by widespread reductions in endogenous Class I, Class II, and TAAR receptor transcripts and proteins, indicating that cis-regulatory elements govern the probability of OR selection. The abundance of OR10G4-expressing cilia enabled highly sensitive ligand screening using CELIA (Cilia-based Evaluation of Ligands and receptor InterActions). Profiling guaiacol derivatives revealed a strong correspondence among receptor activation, cAMP production, and published human psychophysical responses. Although OR10G4 responds to guaiacol-related odorants, multiple canonical vanilla odorants failed to activate the receptor, arguing against a primary role in vanilla perception. Instead, the lowest EC50 ligands were enriched for compounds human subjects described as smoky. Together, these findings link activation of a single human odorant receptor to a defined perceptual odor-quality dimension and establish a general strategy for decoding the molecular basis of human odor perception.
ER -