scholarly journals Extraoral bitter taste receptors in health and disease

2017 ◽  
Vol 149 (2) ◽  
pp. 181-197 ◽  
Author(s):  
Ping Lu ◽  
Cheng-Hai Zhang ◽  
Lawrence M. Lifshitz ◽  
Ronghua ZhuGe
Keyword(s):  
Innate Immunity ◽  
Bitter Taste ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Taste Perception ◽  
Taste Receptors ◽  
Human Disorders ◽  
Health And Disease ◽  
Bitter Taste Receptors ◽  
G Protein Coupled

Bitter taste receptors (TAS2Rs or T2Rs) belong to the superfamily of seven-transmembrane G protein–coupled receptors, which are the targets of >50% of drugs currently on the market. Canonically, T2Rs are located in taste buds of the tongue, where they initiate bitter taste perception. However, accumulating evidence indicates that T2Rs are widely expressed throughout the body and mediate diverse nontasting roles through various specialized mechanisms. It has also become apparent that T2Rs and their polymorphisms are associated with human disorders. In this review, we summarize the physiological and pathophysiological roles that extraoral T2Rs play in processes as diverse as innate immunity and reproduction, and the major challenges in this emerging field.

scholarly journals Advanced Glycation End-Products Can Activate or Block Bitter Taste Receptors

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1317 ◽  
Author(s):  
Appalaraju Jaggupilli ◽  
Ryan Howard ◽  
Rotimi E. Aluko ◽  
Prashen Chelikani
Keyword(s):  
Advanced Glycation End Products ◽  
Bitter Taste ◽  
The Body ◽  
Taste Perception ◽  
Taste Receptors ◽  
Binding Affinities ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Bitter Taste Receptors

Bitter taste receptors (T2Rs) are expressed in several tissues of the body and are involved in a variety of roles apart from bitter taste perception. Advanced glycation end-products (AGEs) are produced by glycation of amino acids in proteins. There are varying sources of AGEs, including dietary food products, as well as endogenous reactions within our body. Whether these AGEs are T2R ligands remains to be characterized. In this study, we selected two AGEs, namely, glyoxal-derived lysine dimer (GOLD) and carboxymethyllysine (CML), based on their predicted interaction with the well-studied T2R4, and its physiochemical properties. Results showed predicted binding affinities (Kd) for GOLD and CML towards T2R4 in the nM and μM range, respectively. Calcium mobilization assays showed that GOLD inhibited quinine activation of T2R4 with IC50 10.52 ± 4.7 μM, whilst CML was less effective with IC50 32.62 ± 9.5 μM. To characterize whether this antagonism was specific to quinine activated T2R4 or applicable to other T2Rs, we selected T2R14 and T2R20, which are expressed at significant levels in different human tissues. A similar effect of GOLD was observed with T2R14; and in contrast, GOLD and CML activated T2R20 with an EC50 of 79.35 ± 29.16 μM and 65.31 ± 17.79 μM, respectively. In this study, we identified AGEs as novel T2R ligands that caused either activation or inhibition of different T2Rs.

scholarly journals The short third intracellular loop and cytoplasmic tail of bitter taste receptors provide functionally relevant GRK phosphorylation sites in TAS2R14

2020 ◽  
pp. jbc.RA120.016056
Author(s):  
Donghwa Kim ◽  
Maria Castaño ◽  
Lauren K Lujan ◽  
Jung A. Woo ◽  
Stephen B. Liggett
Keyword(s):  
Bitter Taste ◽  
Taste Receptors ◽  
Intracellular Loop ◽  
Early Endosomes ◽  
Bitter Taste Receptors ◽  
Novel Target ◽  
Intracellular Loops ◽  
G Protein Coupled ◽  
Gst Fusion Proteins

For most GPCRs, the third intracellular loops (IL3) and C-terminal tails (CT) are sites for GRK-mediated phosphorylation, leading to b-arrestin binding and agonist-specific desensitization. These regions of the G protein-coupled bitter taste receptors (TAS2Rs) are short compared to the superfamily, and their functional role is unclear. TAS2R14 expressed on human airway smooth muscle (HASM) cells relax the cell, suggesting a novel target for bronchodilators. To assess IL3 and CT in agonist-promoted TAS2R14 desensitization (tachyphylaxis), we generated GST-fusion proteins of both the WT sequence and Ala substituted for Ser/Thr in the IL3 and CT sequences. In vitro, activated GRK2 phosphorylated both WT IL3 and WT CT proteins but not Ala-substituted forms. Next, TAS2R14s with mutations in IL3 (IL-5A), CT (CT-5A) and in both regions (IL/CT-10A) were expressed in HEK-293T cells. IL/CT-10A and CT-5A failed to undergo desensitization of the [Ca2+]i response compared to WT, indicating functional desensitization by GRK-phosphorylation is at residues in the CT. Short-term desensitization of TAS2R14 was blocked by GRK2 knockdown in HASM cells. Receptor:b-arrestin binding was absent with IL/CT-10A and CT-5A, but was also reduced in IL-5A, indicating a role for IL3 phosphorylation in the b-arrestin interaction for this function. Agonist-promoted internalization of IL-5A and CT-5A receptors was impaired and these receptors failed to colocalize with early endosomes. These results show that agonist-promoted functional desensitization of TAS2R14 occurs by GRK phosphorylation of CT residues and b-arrestin binding. However, b-arrestin function in the internalization and trafficking of the receptor requires cooperative GRK phosphorylation of IL3 and CT residues.

scholarly journals Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors

2019 ◽  
Vol 20 (6) ◽  
pp. 1402 ◽  
Author(s):  
Antonella Di Pizio ◽  
Maik Behrens ◽  
Dietmar Krautwurst
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Current Knowledge ◽  
Chemical Space ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Odorant Receptors ◽  
Taste Receptors ◽  
Umami Taste ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) belong to the largest class of drug targets. Approximately half of the members of the human GPCR superfamily are chemosensory receptors, including odorant receptors (ORs), trace amine-associated receptors (TAARs), bitter taste receptors (TAS2Rs), sweet and umami taste receptors (TAS1Rs). Interestingly, these chemosensory GPCRs (csGPCRs) are expressed in several tissues of the body where they are supposed to play a role in biological functions other than chemosensation. Despite their abundance and physiological/pathological relevance, the druggability of csGPCRs has been suggested but not fully characterized. Here, we aim to explore the potential of targeting csGPCRs to treat diseases by reviewing the current knowledge of csGPCRs expressed throughout the body and by analysing the chemical space and the drug-likeness of flavour molecules.

scholarly journals Solitary chemosensory cells in the respiratory and vomeronasal epithelium of the human nose: a pilot study

2011 ◽  
Vol 49 (5) ◽  
pp. 507-512
Author(s):  
Thomas Braun ◽  
Brigitte Mack ◽  
Matthias F. Kramer
Keyword(s):  
G Protein ◽  
Bitter Taste ◽  
Vomeronasal Organ ◽  
G Protein Coupled Receptors ◽  
Taste Receptors ◽  
Tissue Samples ◽  
Taste Transduction ◽  
Solitary Chemosensory Cells ◽  
G Protein Coupled ◽  
Human Nose

Background: Recently, solitary chemosensory cells have been described in the respiratory and vomeronasal epithelium of the rodent nose. Expressing G-protein coupled receptors for sweet, umami and bitter taste transduction, these cells are thought to mediate trigeminal reflexes upon stimulation with chemical irritants. The present study analyzes human nasal mucosa for the presence of solitary chemosensory cells. Methodology: In human tissue samples from respiratory mucosa and the vomeronasal organ, gene expression of taste receptors families was studied in five patients using the Affymetrix Human Gene 1.0 ST Array and immunohistochemistry with specific antibodies. Results: Immunohistochemistry revealed that solitary chemosensory cells expressing G-protein coupled receptors for sweet, umami and bitter taste transduction are present in the human nose. cDNA microarray analysis congruently showed that cells expressing bitter taste receptors accumulate in the vomeronasal organ compared to the respiratory epithelium. Conclusions: Solitary chemosensory cells expressing taste receptors are also present in the human nose. Since they are thought to mediate trigeminal reflexes, their role in the pathogenesis of nasal hyperreagibility should be elucidated in further studies.

scholarly journals Structure-Function Analyses of Human Bitter Taste Receptors—Where Do We Stand?

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4423
Author(s):  
Maik Behrens ◽  
Florian Ziegler
Keyword(s):  
Drug Discovery ◽  
Structure Function ◽  
Metabolic Regulation ◽  
Bitter Taste ◽  
Current Knowledge ◽  
Respiratory Control ◽  
Detailed Knowledge ◽  
Taste Receptors ◽  
Bitter Taste Receptors ◽  
G Protein Coupled

The finding that bitter taste receptors are expressed in numerous tissues outside the oral cavity and fulfill important roles in metabolic regulation, innate immunity and respiratory control, have made these receptors important targets for drug discovery. Efficient drug discovery depends heavily on detailed knowledge on structure-function-relationships of the target receptors. Unfortunately, experimental structures of bitter taste receptors are still lacking, and hence, the field relies mostly on structures obtained by molecular modeling combined with functional experiments and point mutageneses. The present article summarizes the current knowledge on the structure–function relationships of human bitter taste receptors. Although these receptors are difficult to express in heterologous systems and their homology with other G protein-coupled receptors is very low, detailed information are available at least for some of these receptors.

scholarly journals BitterMatch: Recommendation systems for matching molecules with bitter taste receptors

2022 ◽  
Author(s):  
Eitan Margulis ◽  
Yuli Slavutsky ◽  
Tatjana Lang ◽  
Mike Behrens ◽  
Yuval Benjamini ◽  
...  
Keyword(s):  
Experimental Data ◽  
Bitter Taste ◽  
Recommendation Systems ◽  
G Protein Coupled Receptors ◽  
Taste Receptors ◽  
Drug Compliance ◽  
G Protein Coupled ◽  
Hybrid Recommendation

Bitterness is an aversive cue elicited by thousands of chemically diverse compounds. Bitter taste may prevent consumption of foods and jeopardize drug compliance. The G protein-coupled receptors for bitter taste, TAS2Rs, have species-dependent number of subtypes and varying expression levels in extraoral tissues. Molecular recognition by TAS2R subtypes is physiologically important, and presents a challenging case study for ligand-receptor matchmaking. Inspired by hybrid recommendation systems, we developed a new set of similarity features, and created the BitterMatch algorithm that predicts associations of ligands to receptors with ~80% precision at ~50% recall. Associations for several compounds were tested in-vitro, resulting in 80% precision and 42% recall. The encouraging performance was achieved by including receptor properties and integrating experimentally determined ligand-receptor associations with chemical ligand-to-ligand similarities. BitterMatch can predict off-targets for bitter drugs, identify novel ligands and guide flavor design. Inclusion of neighbor-informed similarities improves as experimental data mounts, and provides a generalizable framework for molecule-biotarget matching.

scholarly journals Solitary chemosensory cells in the respiratory and vomeronasal epithelium of the human nose: a pilot study

2011 ◽  
Vol 49 (5) ◽  
pp. 507-512
Author(s):  
Thomas Braun ◽  
Brigitte Mack ◽  
Matthias F. Kramer
Keyword(s):  
G Protein ◽  
Bitter Taste ◽  
Vomeronasal Organ ◽  
G Protein Coupled Receptors ◽  
Taste Receptors ◽  
Tissue Samples ◽  
Taste Transduction ◽  
Solitary Chemosensory Cells ◽  
G Protein Coupled ◽  
Human Nose

Background: Recently, solitary chemosensory cells have been described in the respiratory and vomeronasal epithelium of the rodent nose. Expressing G-protein coupled receptors for sweet, umami and bitter taste transduction, these cells are thought to mediate trigeminal reflexes upon stimulation with chemical irritants. The present study analyzes human nasal mucosa for the presence of solitary chemosensory cells. Methodology: In human tissue samples from respiratory mucosa and the vomeronasal organ, gene expression of taste receptors families was studied in five patients using the Affymetrix Human Gene 1.0 ST Array and immunohistochemistry with specific antibodies. Results: Immunohistochemistry revealed that solitary chemosensory cells expressing G-protein coupled receptors for sweet, umami and bitter taste transduction are present in the human nose. cDNA microarray analysis congruently showed that cells expressing bitter taste receptors accumulate in the vomeronasal organ compared to the respiratory epithelium. Conclusions: Solitary chemosensory cells expressing taste receptors are also present in the human nose. Since they are thought to mediate trigeminal reflexes, their role in the pathogenesis of nasal hyperreagibility should be elucidated in further studies.

scholarly journals Construction of a bioluminescence-based assay for bitter taste receptors (TAS2Rs)

2021 ◽  
Author(s):  
Shi Min Tan ◽  
Wei-Guang Seetoh
Keyword(s):  
Calcium Release ◽  
Bitter Taste ◽  
Taste Perception ◽  
Free Calcium ◽  
Taste Receptors ◽  
Signal Transducers ◽  
Functional Studies ◽  
Causative Agents ◽  
Bitter Taste Receptors ◽  
Development And Validation

In humans, a family of 25 bitter taste receptors (TAS2Rs) mediates bitter taste perception. A common approach to characterize bitter causative agents involves expressing TAS2Rs and the appropriate signal transducers in heterologous cell systems, and monitoring changes in the intracellular free calcium levels upon ligand exposure using a fluorescence-based modality. However, a fluorescence-based assay typically suffers from a low signal window, and is susceptible to interference by autofluorescence, therefore limiting its application to screening of plant or food extracts, which are likely to contain autofluorescent compounds. Here, we report the development and validation of a bioluminescence-based intracellular calcium release assay for TAS2Rs that has a better assay performance than a fluorescence-based assay. Furthermore, the bioluminescence-based assay enables the evaluation of TAS2R agonists within an autofluorescent matrix, highlighting its potential utility in the assessment of the bitterness-inducing properties of plant or food fractions by the food industry. Additionally, further improvement to the bioluminescence-based assay for some TAS2Rs was achieved by altering their N-terminal signal sequences, leading to signal window enhancement. Altogether, the bioluminescence-based TAS2R assay can be used to perform functional studies of TAS2Rs, evaluate TAS2R-modulating properties of autofluorescent samples, and facilitate the discovery of compounds that can function as promising bitter taste modulators.

scholarly journals Functional Microswitches of Mammalian G Protein-Coupled Bitter-Taste Receptors

2020 ◽  
Author(s):  
Jérémie Topin ◽  
Cédric Bouysset ◽  
Yiseul Kim ◽  
MeeRa Rhyu ◽  
Sébastien Fiorucci ◽  
...  
Keyword(s):  
G Protein ◽  
Bitter Taste ◽  
Current Knowledge ◽  
Receptor Activation ◽  
Amino Acid Sequences ◽  
Site Directed Mutagenesis ◽  
Taste Receptors ◽  
Bitter Taste Receptors ◽  
G Protein Coupled

AbstractBitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCR). No experimental structure of these receptors is available and key-residues controlling their function remain mostly unknown. Here, we have identified the functional microswitches that encode agonist sensing and downstream signaling mechanisms within TAS2Rs sequences. We thoroughly re-aligned the amino-acid sequences of the 25 human TAS2Rs considering residue conservations and all the experimental data from the literature as constraints. As a test case, an accurate homology model of TAS2R16 was constructed and examined by site-directed mutagenesis and in vitro functional assays. Conserved motifs acting as microswitches during agonist-sensing and receptor activation were pinpointed by comparison with the current knowledge on class A GPCRs. Unravelling these sequence – function relationships is of utmost importance to streamline how TAS2Rs functions are encrypted in their sequence.

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