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 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.

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 Vanillin Activates Human Bitter Taste Receptors TAS2R14, TAS2R20, and TAS2R39

2021 ◽  
Vol 8 ◽  
Author(s):  
Gabriella Morini ◽  
Marcel Winnig ◽  
Timo Vennegeerts ◽  
Gigliola Borgonovo ◽  
Angela Bassoli
Keyword(s):  
Molecular Mechanism ◽  
Bitter Taste ◽  
Sensory Profile ◽  
Food Preparation ◽  
Taste Receptors ◽  
Food Ingredient ◽  
Pharmaceutical Applications ◽  
Starting Point ◽  
Bitter Taste Receptors

Vanilla is widely used in food preparation worldwide for its sensory properties, mainly related to its fragrance, being vanillin the major compound present in the processed vanilla. Vanillin is also known to elicit bitterness as a secondary sensory sensation, but the molecular mechanism of its bitterness has never been reported. Assay buffers of vanillin were tested in vitro on all known 25 human bitter taste receptors TAS2Rs. Three receptors, TAS2R14, TAS2R20, and TAS2R39, were activated, showing that these receptors are mediating the bitterness of vanillin. The result could be useful to improve the overall sensory profile of this broadly used food ingredient, but even more could represent the starting point for further studies to investigate the potential of vanillin in sensory nutrition and other pharmaceutical applications.

scholarly journals Glucosinolates in Sisymbrium officinale (L.) Scop.: Comparative Analysis in Cultivated and Wild Plants and in Vitro Assays with T2Rs Bitter Taste Receptors

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4572
Author(s):  
Gigliola Borgonovo ◽  
Nathan Zimbaldi ◽  
Marta Guarise ◽  
Floriana Bedussi ◽  
Marcel Winnig ◽  
...  
Keyword(s):  
High Performance ◽  
Bitter Taste ◽  
Storage Conditions ◽  
Wild Plants ◽  
Wild Plant ◽  
In Vitro Assays ◽  
Taste Receptors ◽  
Comparable Amount ◽  
Bitter Taste Receptors

Sisymbrium officinale (L.) Scop., commonly known as “hedge mustard” or “the singer’s plant” is a wild plant common in Eurasian regions. Its cultivation is mainly dedicated to herboristic applications and it has only recently been introduced into Italy. The active botanicals in S. officinale are glucosinolates, generally estimated by using UV or high-performance liquid chromatography (HPLC). Using both techniques, we measured the total glucosinolates from S. officinale in different parts of the plant as roots, leaves, seeds, and flowers. A comparison was made for cultivated and wild samples, and for samples obtained with different pre-treatment and fresh, frozen, and dried storage conditions. Cultivated and wild plants have a comparable amount of total glucosinolates, while drying procedures can reduce the final glucosinolates content. The content in glucoputranjivin, which is the chemical marker for glucosinolates in S. officinale, has been determined using HPLC and a pure reference standard. Glucoputranjivin and two isothiocyanates from S. officinale have been submitted to in vitro assays with the platform of bitter taste receptors of the T2Rs family. The results show that glucoputranjivin is a selective agonist of receptor T2R16.

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 Bitter taste receptors of the common vampire bat are functional and show conserved responses to metal ions in vitro

2021 ◽  
Vol 288 (1947) ◽  
Author(s):  
Florian Ziegler ◽  
Maik Behrens
Keyword(s):  
Metal Ions ◽  
Bitter Taste ◽  
Prey Selection ◽  
Taste Receptor ◽  
Food Sources ◽  
Taste Receptors ◽  
Vampire Bats ◽  
Bitter Taste Receptors ◽  
Vampire Bat

The bitter taste sensation is important to warn mammals of the ingestion of potentially toxic food compounds. For mammals, whose nutrition relies on highly specific food sources, such as blood in the case of vampire bats, it is unknown if bitter sensing is involved in prey selection. By contrast to other bat species, vampire bats exhibit numerous bitter taste receptor pseudogenes, which could point to a decreased importance of bitter taste. However, electrophysiological and behavioural studies suggest the existence of functional bitter taste transmission. To determine the agonist spectra of the three bitter taste receptors that are conserved in all three vampire bat species, we investigated the in vitro activation of Desmodus rotundus T2R1, T2R4 and T2R7. Using a set of 57 natural and synthetic bitter compounds, we were able to identify agonists for all three receptors. Hence, we confirmed a persisting functionality and, consequently, a putative biological role of bitter taste receptors in vampire bats. Furthermore, the activation of the human TAS2R7 by metal ions is shown to be conserved in D. rotundus .

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 The Role of Bitter Taste Receptors in Cancer: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5891
Author(s):  
Sofie Zehentner ◽  
Agnes T. Reiner ◽  
Christoph Grimm ◽  
Veronika Somoza
Keyword(s):  
Bitter Taste ◽  
Current Evidence ◽  
Migration And Invasion ◽  
Systematic Research ◽  
Taste Receptors ◽  
Tissue Samples ◽  
Bitter Taste Receptors

Background: Since it is known that bitter taste receptors (TAS2Rs) are expressed and functionally active in various extra-oral cells, their genetic variability and functional response initiated by their activation have become of broader interest, including in the context of cancer. Methods: A systematic research was performed in PubMed and Google Scholar to identify relevant publications concerning the role of TAS2Rs in cancer. Results: While the findings on variations of TAS2R genotypes and phenotypes and their association to the risk of developing cancer are still inconclusive, gene expression analyses revealed that TAS2Rs are expressed and some of them are predominately downregulated in cancerous compared to non-cancerous cell lines and tissue samples. Additionally, receptor-specific, agonist-mediated activation induced various anti-cancer effects, such as decreased cell proliferation, migration, and invasion, as well as increased apoptosis. Furthermore, the overexpression of TAS2Rs resulted in a decreased tumour incidence in an in vivo study and TAS2R activation could even enhance the therapeutic effect of chemotherapeutics in vitro. Finally, higher expression levels of TAS2Rs in primary cancerous cells and tissues were associated with an improved prognosis in humans. Conclusion: Since current evidence demonstrates a functional role of TAS2Rs in carcinogenesis, further studies should exploit their potential as (co-)targets of chemotherapeutics.

scholarly journals Bitter Taste Receptors as Regulators of Abdominal Muscles Contraction

2019 ◽  
pp. 991-995
Author(s):  
P. Zagorchev ◽  
G.V. Petkov ◽  
H.S. Gagov
Keyword(s):  
Skeletal Muscles ◽  
Bitter Taste ◽  
Specific Inhibitor ◽  
Electrical Field Stimulation ◽  
Inhibitory Effect ◽  
Abdominal Muscles ◽  
Taste Receptors ◽  
Bitter Taste Receptors

Bitter taste receptors (TAS2R) are expressed in many non-sensor tissues including skeletal muscles but their function remains unexplored. The aim of this study is to investigate the role of TAS2R in rat abdominal skeletal muscles contractions using denatonium, a TAS2R agonist. Low concentration of denatonium (0.01 mmol/l) caused a significant decrease of amplitudes of the electrical field stimulation (EFS)-induced contractions in abdominal skeletal muscles preparations in vitro. This inhibitory effect was significantly reduced when the preparations were pre-incubated with gentamicin (0.02 mmol/l) used as a non-specific inhibitor of IP3 formation or with BaCl(2) (0.03 mmol/l) applied to block the inward-rectifier potassium current. All experiments were performed in the presence of pipecuronium in order to block the nerve stimulation of the contractions. The data obtained suggest that denatonium decreases the force of rat abdominal muscles contractions mainly via activation of TAS2R, phosphatidylinositol 4,5-biphosphate and its downstream signal metabolites.

Sign in / Sign up

Export Citation Format

Share Document