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Exploring Extranasal Odorant Receptors

Antonella Di Pizio, Ph.D and Jen Pluznick, Ph.D.
February 16, 2023 | 2:00 PM ET



Odorant receptors (ORs) are expressed not only in the olfactory epithelium but also play important roles in extranasal tissues. However, a poor understanding of OR ligands has restricted our ability to fully explore the extranasal role of these receptors. Here, we will discuss efforts to better understand both OR ligands and extranasal OR functions.

Ligands of Odorant Receptors Outside the Odor Space
Antonella Di Pizio, Ph.D.
In Silico Biology and Machine Learning
Leibniz Institute for Food Systems Biology at the Technical University of Munich

With approximately 400 encoding genes in humans, odorant receptors (ORs) are the largest subfamily of class A G-protein-coupled receptors. Despite its high relevance and representation, the odorant-GPCRome is structurally poorly characterized: no experimental structures are available, and the receptive of most ORs is unknown. Computational methods, taking advantage of the most recent AI applications, are effective tools to model the 3D structure of odorant receptors and rationally predict new ligands. Indeed, we showed that computational structural models of ORs can reach high performance in virtual screening campaigns. We also found that ORs can accommodate ligands that exempt the odor space, suggesting the use of integrated structural bioinformatics and chemoinformatics to explore the chemical space of OR ligands to target extranasal ORs.

Unexpected Roles for Extranasal Odorant Receptors
Jen Pluznick, Ph.D.
Dept of Physiology
Johns Hopkins School of Medicine

Odorant receptors (ORs) comprise the largest gene family in the genome and act to mediate olfaction in the olfactory epithelium. However, this gene family is poorly studied outside of the olfactory epithelium, where these receptors can also play critical roles. We have recently identified that an evolutionarily-conserved extranasal OR, Olfr558, is expressed in blood vessels. This receptor has a number of known ligands, some of which are produced by the gut microbiota, but additional efforts are needed to identify which of these ligands is most physiologically relevant in vivo. Intriguingly, we find that Olfr558 is required for sex differences in blood pressure: typically, males have blood pressure that is ~10mmHg higher than that of females, but, this sex difference is entirely absent in Olfr558 KO mice.

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