Ligand Specificity and Evolution of Mammalian Musk Odor Receptors: Effect of Single Receptor Deletion on Odor Detection

Sato-Akuhara, Narumi; Horio, Nao; Kato-Namba, Aya; Yoshikawa, Keiichi; Niimura, Yoshihito; Ihara, Sayoko; Shirasu, Mika; Touhara, Kazushige

doi:10.1523/jneurosci.3259-15.2016

Cited by 67 publications

(91 citation statements)

References 30 publications

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“…Deleting olfr1440 has been reported to produce a much larger detection deficit than what we observe via thresholding 9 . To test whether this is attributable to the different assays, we measured the sensitivity of our ΔT2-9 mice using a similar investigationbased assay ( Supplementary Fig.…”

Section: Sensitivity Deficit From a Single Odorant Receptor Deletioncontrasting

confidence: 47%

“…To compare the detection deficits from TAAR deletions with deficits from deleting canonical ORs, we characterized the effect of deleting a model class II OR, Olfr1440 (MOR215-1). Deletion of Olfr1440 has been reported to reduce sensitivity to muscone as measured using an investigation-based behavioral assay in freely moving mice 9 . We generated a strain of mice (ΔOlfr1440) by CRISPR/Cas9-mediated gene editing, in which the Olfr1440 coding sequence is truncated due to a frameshift and premature stop codon ( Figure 3a).…”

Section: Sensitivity Deficit From a Single Odorant Receptor Deletionmentioning

confidence: 99%

“…Part of this disparity may be attributed to long-standing difficulties in functionally expressing olfactory receptors and identifying the most sensitive (threshold-determining) receptors for specific odorants. While previous experiments have shown detection deficits by removing individual (or sets of) olfactory receptors 9,10,11 , in most species (particularly in mammals) it remains unclear what factors (e.g. receptor sensitivity, sensory neuron number, glomerular convergence) influence behavioral detection thresholds.…”

Section: Introductionmentioning

confidence: 97%

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Single olfactory receptors set odor detection thresholds

Dewan¹,

Cichy²,

Zhang³

et al. 2018

Preprint

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Menzie for technical support, and William Kath and Rosemary Braun for statistical advice. We acknowledge Lynn Doglio and the Transgenesis and Targeted Mutagenesis Laboratory at Northwestern University for transgenic mouse production. Contributions A.D. and T.B conceived the project. A.D., D.R. and T.B. designed the experiments and the behavioral setups. A.D. performed all behavioral experiments and data analysis. A.C. performed in vivo imaging experiments and analysis. J.Z. performed electrophysiological recordings and analysis. K.M performed DREAM experiments and analysis. P.F. conceived the transgenic strategy and helped generate the receptor overexpressing mice. A.D. and T.B. wrote the manuscript with input from all authors. The authors declare no competing interests. 2 ABSTRACTIn many species, survival depends on olfaction, yet the mechanisms that underlie olfactory sensitivity are not well understood. Here, we examine how a conserved subset of olfactory receptors, the trace amine-associated receptors (TAARs) determine odor detection thresholds of mice to amines. We find that deleting all TAARs, or even single TAARs, results in significant odor detection deficits. This finding is not limited to TAARs, as the deletion of a canonical odorant receptor reduced behavioral sensitivity to its preferred ligand. Remarkably, behavioral threshold is set solely by the most sensitive receptor, with no contribution from other highly sensitive receptors. In addition, increasing the number of sensory neurons (and glomeruli) expressing a threshold-determining TAAR does not improve detection, indicating that sensitivity is not limited by the typical complement of sensory neurons. Our findings demonstrate that olfactory thresholds are set by the single highest affinity receptor, and suggest that TAARs are evolutionarily conserved because they determine the sensitivity to a class of biologically relevant chemicals.

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Section: Sensitivity Deficit From a Single Odorant Receptor Deletioncontrasting

confidence: 47%

Section: Sensitivity Deficit From a Single Odorant Receptor Deletionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Single olfactory receptors set odor detection thresholds

Dewan¹,

Cichy²,

Zhang³

et al. 2018

Preprint

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“…33 While experiments with OR5AN1 are done with cells in a dish rather than within whole organisms, scientists have successfully used HEK cells to study rhodopsin and adrenaline receptors and such systems are considered the standard in studying ORs. 35 Examples of discrimination of isotopologues by insects have been reported, 36 some of which are at the behavioral and not at the receptor level.…”

Section: Theories Of Olfactionmentioning

confidence: 99%

The role of metals in mammalian olfaction of low molecular weight organosulfur compounds

et al. 2017

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While suggestions concerning the possible role of metals in olfaction and taste date back 50 years, only recently has it been possible to confirm these proposals with experiments involving individual olfactory receptors (ORs). A detailed discussion of recent experimental results demonstrating the key role of metals in enhancing the response of human and other vertebrate ORs to specific odorants is presented against the backdrop of our knowledge of how the sense of smell functions both at the molecular and whole animal levels. This review emphasizes the role of metals in the detection of low molecular weight thiols, sulfides, and other organosulfur compounds, including those found in strong-smelling animal excretions and plant volatiles, and those used in gas odorization. Alternative theories of olfaction are described, with evidence favoring the modified “shape” theory. The use of quantum mechanical/molecular modeling (QM/MM), site-directed mutagenesis and saturation-transfer-difference (STD) NMR is discussed, providing support for biological studies of mouse and human receptors, MOR244-3 and OR OR2T11, respectively. Copper is bound at the active site of MOR244-3 by cysteine and histidine, while cysteine, histidine and methionine are involved with OR2T11. The binding pockets of these two receptors are found in different locations in the three-dimensional seven transmembrane models. Another recently deorphaned human olfactory receptor, OR2M3, highly selective for a thiol from onions, and a broadly-tuned thiol receptor, OR1A1, are also discussed. Other topics covered include the effects of nanoparticles and heavy metal toxicants on vertebrate and fish ORs, intranasal zinc products and the loss of smell (anosmia).

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“…It teased out residues that are specific for each odorant, which is essential for understanding how chemically similar odorants are differentiated by the OR family with high specificity/selectivity. So far, research focusing on subtle selectivity has mostly employed site-directed mutagenesis and molecular modeling of individual ORs, namely hOR17-4 for lilial and bourgenoal analogues 33 , hOR1A1 for R-/S-carvone enantiomers 34 , hOR5AN1 and mOR215-1 for musk odorants 35 , mOR-EG for eugenol 36 , and our recent study on zebrafish ORs for bile acids/salts 37 .…”

Section: Discussionmentioning

confidence: 99%

Functions of olfactory receptors are decoded from their sequence

Cong

Ren

Pacalon

et al. 2020

Preprint

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G protein-coupled receptors (GPCRs) conserve common structural folds and activation mechanisms, yet their ligand spectra and functions are highly diversified. This work investigated how the functional variations in olfactory GPCRs (ORs)−the largest GPCR family−are encoded in the primary sequence. With the aid of site-directed mutagenesis and molecular simulations, we built machine learning models to predict OR-ligand pairs as well as basal activity of ORs. In vitro functional assay confirmed 20 new OR-odorant pairs, including 9 orphan ORs. Residues around the odorant-binding pocket dictate the odorant selectivity/specificity of the ORs. Residues that encode the varied basal activities of the ORs were found to mostly surround the conserved motifs as well as the binding pocket. The machine learning approach, which is readily applicable to mammalian OR families, will accelerate OR-odorant mapping and the decoding of combinatorial OR codes for odors. IntroductionFunctions of proteins are encoded within either diversified or conserved subparts of their sequence. G protein-coupled receptors (GPCRs) are the most remarkable examples of this phenomenon. GPCRs are the largest membrane protein family and the targets of about 40% of marketed drugs 1 . The human genome contains over 800 genes coding for GPCRs, which exert differentiated and specific functions in the complex cellular signaling network. Half of these genes are olfactory receptors (ORs), which endow us with fascinating capacities of odor discrimination 2,3 . Mammalian GPCRs conserve a typical structural architecture of seven transmembrane helices (7TM) that house an orthosteric ligand-binding pocket 4 . Their intrinsic signaling mechanism, large-scale conformational changes to accommodate their cognate G proteins, is encoded in conserved motifs throughout the 7TM, which form a network of inter-TM contacts converging to their cytoplasmic part 5 . Namely, the "D(E)RY", "CWLP" and "NPxxY" motifs in TM3, TM6 and TM7, respectively, are the most conserved hubs of the allosteric communication between the orthosteric pocket and the cytoplasmic side of class A GPCRs 4 . The rest of the GPCR sequences, especially the ligand-binding pocket, have diversified extensively, which resulted in huge variations in the receptors' function. Amongst the hundreds of variable residues in the GPCR sequences, it is very likely that some are specialized for the receptors' ligand specificity/selectivity while, others encode more information on the receptors' intrinsic activity.This study focused on the divergence of ligand-dependent and ligand-independent (or basal) activities of olfactory class A GPCRs. We seek to identify amino acid positions that are critical for the receptors' functional heterogeneity. ORs discriminate a vast spectrum of volatile molecules (odorants) and code for an innumerous number of odors perceived in the brain. The manyto-many relationships between ORs and odorants are key to understanding odor perception 6 . ORs are also expressed ectopically, some of which have ...

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Ligand Specificity and Evolution of Mammalian Musk Odor Receptors: Effect of Single Receptor Deletion on Odor Detection

Cited by 67 publications

References 30 publications

Single olfactory receptors set odor detection thresholds

Single olfactory receptors set odor detection thresholds

The role of metals in mammalian olfaction of low molecular weight organosulfur compounds

Functions of olfactory receptors are decoded from their sequence

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