Olfactory receptor antagonism between odorants

Oka, Yuki; Omura, Masayo; Kataoka, Hiroshi; Touhara, Kazushige

doi:10.1038/sj.emboj.7600032

Cited by 245 publications

(206 citation statements)

References 34 publications

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“…One possibility is that these odorants do so by receptor antagonism in the nose. This mechanism would be consistent with previous reports of odorants that can act as antagonists to block the activation of certain ORs or nasal neurons by other odorants (37)(38)(39).…”

Section: Resultssupporting

confidence: 92%

Combinatorial effects of odorants on mouse behavior

Saraiva

Kondoh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

130

160

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The mechanisms by which odors induce instinctive behaviors are largely unknown. Odor detection in the mouse nose is mediated by >1, 000 different odorant receptors (ORs) and trace amine-associated receptors (TAARs). Odor perceptions are encoded combinatorially by ORs and can be altered by slight changes in the combination of activated receptors. However, the stereotyped nature of instinctive odor responses suggests the involvement of specific receptors and genetically programmed neural circuits relatively immune to extraneous odor stimuli and receptor inputs. Here, we report that, contrary to expectation, innate odor-induced behaviors can be context-dependent. First, different ligands for a given TAAR can vary in behavioral effect. Second, when combined, some attractive and aversive odorants neutralize one another's behavioral effects. Both a TAAR ligand and a common odorant block aversion to a predator odor, indicating that this ability is not unique to TAARs and can extend to an aversive response of potential importance to survival. In vitro testing of single receptors with binary odorant mixtures indicates that behavioral blocking can occur without receptor antagonism in the nose. Moreover, genetic ablation of a single receptor prevents its cognate ligand from blocking predator odor aversion, indicating that the blocking requires sensory input from the receptor. Together, these findings indicate that innate odor-induced behaviors can depend on context, that signals from a single receptor can block innate odor aversion, and that instinctive behavioral responses to odors can be modulated by interactions in the brain among signals derived from different receptors.olfaction | behavior | TAAR | odorants

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Section: Resultssupporting

confidence: 92%

Combinatorial effects of odorants on mouse behavior

Saraiva

Kondoh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

130

160

View full text Add to dashboard Cite

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“…This prediction was confirmed in our functional assay. The existence of antagonists for ORs has been shown in a few studies (47,48). Our results with the C12 dicarboxylic acid provide further insight into the role of OR antagonism.…”

Section: Discussionsupporting

confidence: 71%

The Molecular Basis for Ligand Specificity in a Mouse Olfactory Receptor

Abaffy

Malhotra

Luetje

2007

Journal of Biological Chemistry

100

103

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Sequence differences between members of the mouse olfactory receptor MOR42 subfamily (MOR42-3 and MOR42-1) are likely to be the basis for variation in ligand binding preference among these receptors. We investigated the specificity of MOR42-3 for a variety of dicarboxylic acids. We used site-directed mutagenesis, guided by homology modeling and ligand docking studies, to locate functionally important residues. Receptors were expressed in Xenopus oocytes and assayed using high throughput electrophysiology. The importance of the Val-113 residue, located deep within the receptor, was analyzed in the context of interhelical interactions. We also screened additional residues predicted to be involved in ligand binding site, based on comparison of ortholog/paralog pairs from the mouse and human olfactory receptor genomes (Man, O., Gilad, Y., and Lancet, D. (2004) Protein Sci. 13, 240 -254). A network of 8 residues in transmembrane domains III, V, and VI was identified.These residues form part of the ligand binding pocket of MOR42-3. C12 dicarboxylic acid did not activate the receptor in our functional assay, yet our docking simulations predicted its binding site in MOR42-3. Binding without activation implied that C12 dicarboxylic acid might act as an antagonist. In our functional assay, C12 dicarboxylic acid did indeed act as an antagonist of MOR42-3, in agreement with molecular docking studies. Our results demonstrate a powerful approach based on the synergy between computational predictions and physiological assays.

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“…1, available at www.jneurosci.org as supplemental material), three (30%) were to two components, and one (10%) was to three components. Finally, to exclude the possibility that the lack of responses to certain mixtures was attributable to cancellation of responses between mutually inhibitory components (Oka et al, 2004;Tabor et al, 2004), the responses of all (n ϭ 44) cells to individual components of a randomly chosen noneffective mixture were also examined. No responses to individual components in noneffective mixtures were found, reinforcing the idea that mitral cells only respond to a very small fraction of odorants in our panel.…”

Section: Mitral Cells In the Mob Exhibit Narrower Responsiveness Thanmentioning

confidence: 99%