Responsiveness of G protein-coupled odorant receptors is partially attributed to the activation mechanism

Yu, Yiqun; March, Claire A. de; Ni, Mengjue J.; Adipietro, Kaylin A.; Golebiowski, Jérôme; Matsunami, Hiroaki; Ma, Minghong

doi:10.1073/pnas.1517510112

Cited by 48 publications

(73 citation statements)

References 41 publications

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“…However, receptors vary in their copy numbers [58], which implies different average sensitivities, see section E of the S1 Appendix. Additionally, point mutations of a receptor gene can change this receptor’s sensitivities to almost all ligands [59]. Consequently, typical receptor arrays might be heterogeneous, where some receptor types have larger mean sensitivities than others.…”

Section: Resultsmentioning

confidence: 99%

“…This suggests that the sensitivities are tightly controlled and maybe even adjusted to the odor statistics of the environment. On evolutionary time scales, the sensitivities could be regulated by point mutations of the receptors that change how ligands bind [59]. On shorter time scales, the sensitivities could be regulated by changing the receptor copy numbers, see section E of the S1 Appendix.…”

Section: Discussionmentioning

confidence: 99%

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Normalized Neural Representations of Complex Odors

Zwicker

2016

PLoS ONE

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The olfactory system removes correlations in natural odors using a network of inhibitory neurons in the olfactory bulb. It has been proposed that this network integrates the response from all olfactory receptors and inhibits them equally. However, how such global inhibition influences the neural representations of odors is unclear. Here, we study a simple statistical model of the processing in the olfactory bulb, which leads to concentration-invariant, sparse representations of the odor composition. We show that the inhibition strength can be tuned to obtain sparse representations that are still useful to discriminate odors that vary in relative concentration, size, and composition. The model reveals two generic consequences of global inhibition: (i) odors with many molecular species are more difficult to discriminate and (ii) receptor arrays with heterogeneous sensitivities perform badly. Comparing these predictions to experiments will help us to understand the role of global inhibition in shaping normalized odor representations in the olfactory bulb.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Normalized Neural Representations of Complex Odors

Zwicker

2016

PLoS ONE

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“…Immunocytochemisty-To determine the cellular expression levels of mouse Tas2r and their cell surface localization, selected receptor coding sequences (excluding the stop codon) were cloned in pcDNA5/FRT expression vector resulting in Tas2r sequences flanked by the first 60 amino acids of rhodopsin (Rho tag) (117), which can be detected with suitable antisera in vivo (118), and an HSV-tagged epitope at the amino and carboxyl termini, respectively. HEK293T-G␣16gust44 cells were grown and transfected with Rho-tagged receptor plasmids on poly-D-lysine-coated glass coverslips as published previously (1,30,31).…”

Section: Methodsmentioning

confidence: 99%

Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans

Lossow

Hübner

Roudnitzky

et al. 2016

Journal of Biological Chemistry

187

277

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One key to animal survival is the detection and avoidance of potentially harmful compounds by their bitter taste. Variable numbers of taste 2 receptor genes expressed in the gustatory end organs enable bony vertebrates (Euteleostomi) to recognize numerous bitter chemicals. It is believed that the receptive ranges of bitter taste receptor repertoires match the profiles of bitter chemicals that the species encounter in their diets. Human and mouse genomes contain pairs of orthologous bitter receptor genes that have been conserved throughout evolution. Moreover, expansions in both lineages generated species-specific sets of bitter taste receptor genes. It is assumed that the orthologous bitter taste receptor genes mediate the recognition of bitter toxins relevant for both species, whereas the lineagespecific receptors enable the detection of substances differently encountered by mice and humans. By challenging 34 mouse bitter taste receptors with 128 prototypical bitter substances in a heterologous expression system, we identified cognate compounds for 21 receptors, 19 of which were previously orphan receptors. We have demonstrated that mouse taste 2 receptors, like their human counterparts, vary greatly in their breadth of tuning, ranging from very broadly to extremely narrowly tuned receptors. However, when compared with humans, mice possess fewer broadly tuned receptors and an elevated number of narrowly tuned receptors, supporting the idea that a large receptor repertoire is the basis for the evolution of specialized receptors. Moreover, we have demonstrated that sequence-orthologous bitter taste receptors have distinct agonist profiles. Species-specific gene expansions have enabled further diversification of bitter substance recognition spectra.The plethora of natural compounds that taste bitter for humans comprises numerous chemicals with pharmacological activities that can make them powerful toxins, such as the alkaloids strychnine and colchicine or the sesquiterpene lactone picrotoxinin (1). However, compounds believed to exert health-beneficial effects such as the antioxidative phytoestrogen genistein from soy (2), the analgesic drug acetaminophen (3), or various polyphenols also taste bitter (4). To avoid ingestion of bitter substances that would pose a threat to organisms, efficient recognition and rejection mechanisms have developed throughout the animal kingdom. In bony vertebrates (Euteleostomi), the avoidance of bitter compounds is centered on taste receptors that detect potentially harmful substances with high accuracy and adequate sensitivity (5). Vertebrate bitter taste receptors, called taste 2 receptors (TAS2R (human) or Tas2r (murine)), 2 are G protein-coupled receptors only remotely related to other classes of this large and enormously versatile receptor family (6 -10). During evolution the first Tas2r genes appeared in the genomes of bony fish (11). In higher vertebrates frequent independent expansions and pseudogenization events resulted in differently sized Tas2r gene repertoires (12). Cons...

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“…The Dual-Glo Luciferase Assay System (Promega, Madison, Wisconsin, USA) is the most commonly used method for high-throughput screening of odorant receptor pairs [14, 56, 75, 86, 113]. This method quantifies cellular responses as an indirect measure of odorant receptor activation as previously described [117].…”

Section: Methodsmentioning

confidence: 99%

Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor

et al. 2017

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Several studies have demonstrated the expression of odorant receptors (OR) in various human tissues and their involvement in different physiological and pathophysiological processes. However, the functional role of ORs in the human heart is still unclear. Here, we firstly report the functional characterization of an OR in the human heart. Initial next-generation sequencing analysis revealed the OR expression pattern in the adult and fetal human heart and identified the fatty acid-sensing OR51E1 as the most highly expressed OR in both cardiac development stages. An extensive characterization of the OR51E1 ligand profile by luciferase reporter gene activation assay identified 2-ethylhexanoic acid as a receptor antagonist and various structurally related fatty acids as novel OR51E1 ligands, some of which were detected at receptor-activating concentrations in plasma and epicardial adipose tissue. Functional investigation of the endogenous receptor was carried out by Ca2+ imaging of human stem cell-derived cardiomyocytes. Application of OR51E1 ligands induced negative chronotropic effects that depended on activation of the OR. OR51E1 activation also provoked a negative inotropic action in cardiac trabeculae and slice preparations of human explanted ventricles. These findings indicate that OR51E1 may play a role as metabolic regulator of cardiac function.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-017-0600-y) contains supplementary material, which is available to authorized users.

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Responsiveness of G protein-coupled odorant receptors is partially attributed to the activation mechanism

Cited by 48 publications

References 41 publications

Normalized Neural Representations of Complex Odors

Normalized Neural Representations of Complex Odors

Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans

Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor

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