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Despite the important role of bitter taste for the rejection of potentially harmful food sources, birds have long been suspected to exhibit inferior bitter tasting abilities. Although more recent reports on the bitter recognition spectra of several bird species have cast doubt about the validity of this assumption, the bitter taste of avian species is still an understudied field. Previously, we reported the bitter activation profiles of three zebra finch receptors Tas2r5, -r6, and -r7, which represent orthologs of a single chicken bitter taste receptor, Tas2r1. In order to get a better understanding of the bitter tasting capabilities of zebra finches, we selected another Tas2r gene of this species that is similar to another chicken Tas2r. Using functional calcium mobilization experiments, we screened zebra finch Tas2r1 with 72 bitter compounds and observed responses for 7 substances. Interestingly, all but one of the newly identified bitter agonists were different from those previously identified for Tas2r5, -r6, and -r7 suggesting that the newly investigated receptor fills important gaps in the zebra finch bitter recognition profile. The most potent bitter agonist found in our study is cucurbitacin I, a highly toxic natural bitter substance. We conclude that zebra finch exhibits an exquisitely developed bitter taste with pronounced cucurbitacin I sensitivity suggesting a prominent ecological role of this compound for zebra finch. [ABSTRACT FROM AUTHOR]

Taste or gustation is the sense evolving from the chemo-sensory system present in the oral cavity of avian species, which evolved to evaluate the nutritional value of foods by detecting relevant compounds including amino acids and peptides, carbohydrates, lipids, calcium, salts, and toxic or anti-nutritional compounds. In birds compared to mammals, due to the relatively low retention time of food in the oral cavity, the lack of taste papillae in the tongue, and an extremely limited secretion of saliva, the relevance of the avian taste systemhas been historically undermined. However, in recent years, novel data has emerged, facilitated partially by the advent of the genomic era, evidencing that the taste system is ascrucialtoavianspeciesasisto mammals. Despite many similarities, there are also fundamental differences between avian and mammalian taste systems in terms of anatomy, distribution of taste buds, and the nature and molecular structure of taste receptors. Generally, birds have smaller oral cavities and a lower number of taste buds compared to mammals, and their distribution in the oral cavity appears to follow the swallowing pattern of foods. In addition, differences between bird species in the size, structure and distribution of taste buds seem to be associated with diet type and other ecological adaptations. Birds also seem to have a smaller repertoire of bitter taste receptors (T2Rs) and lack some taste receptors such as the T1R2 involved in sweet taste perception. This has opened new areas of research focusing on taste perception mechanisms independent of GPCR taste receptors and the discovery of evolutionary shifts in the molecular function of taste receptors adapting to ecological niches in birds. For example, recent discoveries have shown that the amino acid taste receptor dimer T1R1-T1R3 have mutated to sense simple sugars in almost half of the living bird species, or SGLT1 has been proposed as a part of a T1R2-independent sweet taste sensing in chicken. The aim of this review is to present the scientific data known to date related to the avian taste system across species and its impact on dietary choices including domestic and wild species. [ABSTRACT FROM AUTHOR]

Taste or gustation is the sense evolving from the chemo-sensory system present in the oral cavity of avian species, which evolved to evaluate the nutritional value of foods by detecting relevant compounds including amino acids and peptides, carbohydrates, lipids, calcium, salts, and toxic or anti-nutritional compounds. In birds compared to mammals, due to the relatively low retention time of food in the oral cavity, the lack of taste papillae in the tongue, and an extremely limited secretion of saliva, the relevance of the avian taste system has been historically undermined. However, in recent years, novel data has emerged, facilitated partially by the advent of the genomic era, evidencing that the taste system is as crucial to avian species as is to mammals. Despite many similarities, there are also fundamental differences between avian and mammalian taste systems in terms of anatomy, distribution of taste buds, and the nature and molecular structure of taste receptors. Generally, birds have smaller oral cavities and a lower number of taste buds compared to mammals, and their distribution in the oral cavity appears to follow the swallowing pattern of foods. In addition, differences between bird species in the size, structure and distribution of taste buds seem to be associated with diet type and other ecological adaptations. Birds also seem to have a smaller repertoire of bitter taste receptors (T2Rs) and lack some taste receptors such as the T1R2 involved in sweet taste perception. This has opened new areas of research focusing on taste perception mechanisms independent of GPCR taste receptors and the discovery of evolutionary shifts in the molecular function of taste receptors adapting to ecological niches in birds. For example, recent discoveries have shown that the amino acid taste receptor dimer T1R1-T1R3 have mutated to sense simple sugars in almost half of the living bird species, or SGLT1 has been proposed as a part of a T1R2-independent sweet taste sensing in chicken. The aim of this review is to present the scientific data known to date related to the avian taste system across species and its impact on dietary choices including domestic and wild species.

The receptor potentials of taste receptor cells remain unclear. Here, we demonstrate that taste receptor cells generate oscillating depolarization (n = 7) with action potentials in response to sweet, bitter, umami, and salty taste substances. At a lower concentration of taste substances, taste receptor cells exhibited oscillations in membrane potentials with a low frequency and small magnitude of depolarization. Although the respective waves contained no or 1–2 action potentials, the taste receptor cells generated action potentials continuously in the presence of taste stimuli. Both the frequency and magnitude of oscillations increased when the concentration was increased, to 0.67–1.43 Hz (n = 3) and Δ39–53 mV (n = 3) in magnitude from −64.7 ± 4.2 to −18.7 ± 5.9 mV, which may activate the ATP-permeable ion channels. In contrast, a sour tastant (10-mM HCl) induced membrane depolarization (Δ19.4 ± 9.5 mV, n = 4) with action potentials in type III taste receptor cells. Interestingly, NaCl (1 M) taste stimuli induced oscillation (n = 2) or depolarization (Δ10.5 ± 5.7 mV at the tonic component, n = 9). Our results indicate that the frequency and magnitude of oscillations increased with increasing taste substance concentrations. These parameters may contribute to the expression of taste "thickness." [ABSTRACT FROM AUTHOR]

One of the hallmarks of acute respiratory distress syndrome (ARDS) is an excessive increase in pulmonary vascular permeability. In settings of ARDS, the loss of barrier integrity is mediated by cell–cell contact disassembly and actin remodelling. Studies into molecular mechanisms responsible for improving microvascular barrier function are therefore vital in the development of therapeutic targets for reducing vascular permeability seen in ARDS. Bitter taste receptors (T2Rs) belong to the superfamily of G-protein-coupled receptors found in several extraoral systems, including lung epithelial and smooth muscle cells. In the present study, we show for the first time that several T2Rs are expressed in human pulmonary arterial endothelial cells (HPAECs). Our results focus on those which are highly expressed as: T2R10, T2R14 and T2R38. Agonists for T2R10 (denatonium) and T2R38 (phenylthiourea), but not T2R14 (noscapine), significantly attenuated lipopolysaccharide (LPS)-induced permeability and VE-cadherin internalisation in HPAECs. In T2R10- or T2R38-siRNA knockdown cells, these endothelial-protective effects were abolished, indicating a direct effect of agonists in regulating barrier integrity. Our further findings indicate that T2R10 and T2R38 exert their barrier-protective function through cAMP but via Rac1-dependent and independent pathways, respectively. However, using an in vivo model of ARDS, the T2R38 agonist, phenylthiourea, was not able to protect against pulmonary edema formation. Taken together, these studies identify bitter taste sensing in the pulmonary endothelium to regulate barrier integrity in vitro through cAMP-Rac1 signalling. [ABSTRACT FROM AUTHOR]

Sensory receptors, including olfactory receptors (ORs), taste receptors (TRs), and opsins (Opns) have recently been found in a variety of non-sensory tissues where they have distinct physiological functions. As G protein-coupled receptors (GPCRs), these proteins can serve as important chemosensors by sensing and interpreting chemical cues in the environment. We reasoned that the liver, the largest metabolic organ in the body, is primed to take advantage of some of these sensory receptors in order to sense and regulate blood content and metabolism. In this study, we report the expression of novel hepatic sensory receptors – including 7 ORs, 6 bitter TRs, and 1 Opn – identified through a systematic molecular biology screening approach. We further determined that several of these receptors are expressed within hepatocytes, the parenchymal cells of the liver. Finally, we uncovered several agonists of the previously orphaned hepatic ORs. These compounds fall under two classes: methylpyrazines and monoterpenes. In particular, the latter chemicals are plant and fungal-derived compounds with known hepatic protective effects. Collectively, this study sheds light on the chemosensory functions of the liver and unveils potentially important regulators of hepatic homeostasis.

The human genome contains ∼29 bitter taste receptors (T2Rs), which are responsible for detecting thousands of bitter ligands, including toxic and aversive compounds. This sentinel function varies between individuals and is underpinned by naturally occurring T2R polymorphisms, which have also been associated with disease. Recent studies have reported the expression of T2Rs and their downstream signaling components within non-gustatory tissues, including the heart. Though the precise role of T2Rs in the heart remains unclear, evidence points toward a role in cardiac contractility and overall vascular tone. In this review, we summarize the extra-oral expression of T2Rs, focusing on evidence for expression in heart; we speculate on the range of potential ligands that may activate them; we define the possible signaling pathways they activate; and we argue that their discovery in heart predicts an, as yet, unappreciated cardiac physiology.

The human genome contains ∼29 bitter taste receptors (T2Rs), which are responsible for detecting thousands of bitter ligands, including toxic and aversive compounds. This sentinel function varies between individuals and is underpinned by naturally occurring T2R polymorphisms, which have also been associated with disease. Recent studies have reported the expression of T2Rs and their downstream signaling components within non-gustatory tissues, including the heart. Though the precise role of T2Rs in the heart remains unclear, evidence points toward a role in cardiac contractility and overall vascular tone. In this review, we summarize the extra-oral expression of T2Rs, focusing on evidence for expression in heart; we speculate on the range of potential ligands that may activate them; we define the possible signaling pathways they activate; and we argue that their discovery in heart predicts an, as yet, unappreciated cardiac physiology. [ABSTRACT FROM AUTHOR]

Cells expressing bitter taste receptors (T2Rs or Tas2rs) in extraoral tissues are considered to be chemosensory cells mediating protective responses to potentially harmful or even antiinflammatory or antimicrobial compounds. In a previous study the activity of the Tas2R143/Tas2R135/Tas2r126 cluster promoter in the stomach was monitored using a Cre-reporter mouse line. Reporter gene expression and Tas2r126 mRNA were found in brush cells located at the distal wall of the gastric groove. In this study, we explored whether brush cells and epithelial cells of the stomach in fact contain the Tas2r126 receptor protein. Using immunohistochemistry, we demonstrate the presence of Tas2r126 immunoreactivity in different cell populations in the glandular stomach, in a subset of brush cells at the gastric groove and in unique glandular units as well as in certain enteroendocrine cells. In brush cells at the gastric groove, a strong immunofluorescence signal for the Tas2r126 receptor was observed at the most apical region of the cells, i.e., the microvillar tuft. In addition, we found a high density of Tas2r126-positive brush cells in the unique glandular units. These invaginations are located distally to the groove, open directly into the furrow and are enwrapped by smoothelin-immunoreactive muscles. In the corpus, Tas2r126 immunoreactivity was found in histamine-producing ECL cells and in ghrelin-producing X/A-like cells, the main enteroendcrine cells of this compartment. In the antrum, Tas2r126 labeling was observed in serotonin-storing EC cells and ghrelin cells, both representing only minor populations of enteroendocrine cells in this compartment. In conclusion, our data provide evidence for the presence of the Tas2r126 receptor protein in distinct cell types in the epithelium lining the mouse stomach which render the stomach responsive to agonists for bitter receptors. [ABSTRACT FROM AUTHOR]

Background: Bitter-taste receptors (TAS2Rs) are involved in airway relaxation but are also expressed in human blood leukocytes. We studied TAS2R expression and the effects of TAS2R agonists on the lipopolysaccharide (LPS)-induced cytokine release in human lung macrophages (LMs). Methods: Lung macrophages were isolated from patients undergoing surgery for carcinoma. We used RT-qPCR to measure transcripts of 16 TAS2Rs (TAS2Rs 3/4/5/7/8/9/10/14/19/20/31/38/39/43/45 and 46) in unstimulated and LPS-stimulated (10 ng.mL–1) LMs. The macrophages were also incubated with TAS2R agonists for 24 h. Supernatant levels of the cytokines TNF-α, CCL3, CXCL8 and IL-10 were measured using ELISAs. Results: The transcripts of all 16 TAS2Rs were detected in macrophages. The addition of LPS led to an increase in the expression of most TAS2Rs, which was significant for TAS2R7 and 38. Although the promiscuous TAS2R agonists, quinine and denatonium, inhibited the LPS-induced release of TNF-α, CCL3 and CXCL8, diphenidol was inactive. Partially selective agonists (dapsone, colchicine, strychnine, and chloroquine) and selective agonists [erythromycin (TAS2R10), phenanthroline (TAS2R5), ofloxacin (TAS2R9), and carisoprodol (TAS2R14)] also suppressed the LPS-induced cytokine release. In contrast, two other agonists [sodium cromoglycate (TAS2R20) and saccharin (TAS2R31 and 43)] were inactive. TAS2R agonists suppressed IL-10 production – suggesting that this anti-inflammatory cytokine is not involved in the inhibition of cytokine production. Conclusion: Human LMs expressed TAS2Rs. Experiments with TAS2R agonists' suggested the involvement of TAS2Rs 3, 4, 5, 9, 10, 14, 30, 39 and 40 in the inhibition of cytokine production. TAS2Rs may constitute new drug targets in inflammatory obstructive lung disease. [ABSTRACT FROM AUTHOR]

Clinical management of asthma and chronic obstructive pulmonary disease (COPD) has primarily relied on the use of beta 2 adrenergic receptor agonists (bronchodilators) and corticosteroids, and more recently, monoclonal antibody therapies (biologics) targeting specific cytokines and their functions. Although these approaches provide relief from exacerbations, questions remain on their long-term efficacy and safety. Furthermore, current therapeutics do not address progressive airway remodeling (AR), a key pathological feature of severe obstructive lung disease. Strikingly, agonists of the bitter taste receptors (TAS2Rs) deliver robust bronchodilation, curtail allergen-induced inflammatory responses in the airways and regulate airway smooth muscle (ASM) cell proliferation and mitigate features of AR in vitro and in animal models. The scope of this review is to provide a comprehensive and systematic insight into our current understanding of TAS2Rs with an emphasis on the molecular events that ensue TAS2R activation in distinct airway cell types and expand on the pleiotropic effects of TAS2R targeting in mitigating various pathological features of obstructive lung diseases. Finally, we will discuss specific opportunities that could help the development of selective agonists for specific TAS2R subtypes in the treatment of asthma. [ABSTRACT FROM AUTHOR]

Significant advances have been made in the past decade in mapping the distributions and the physiological functions of extra-oral bitter taste receptors (TAS2Rs) in non-gustatory tissues. In particular, it has been found that TAS2Rs are expressed in various muscle tissues and activation of TAS2Rs can lead to muscle cell relaxation, which suggests that TAS2Rs may be important new targets in muscle relaxation therapy for various muscle-related diseases. So far, however, there is a lack of potent extra-oral TAS2R agonists that can be used as novel drug agents in muscle relaxation therapies. Interestingly, traditional Chinese medicine (TCM) often characterizes a drug's property in terms of five distinct flavors (bitter, sweet, sour, salty, and pungent) according to its taste and function, and commonly regards "bitterness" as an intrinsic property of "good medicine." In addition, many bitter flavored TCM are known in practice to cause muscle relaxation after long term use, and in lab experiments the compounds identified from some bitter flavored TCM do activate TAS2Rs and thus relax muscle cells. Therefore, it is highly possible to discover very useful extra-oral TAS2R agonists for muscle relaxation therapies among the abundant bitter compounds used in bitter flavored TCM. With this perspective, we reviewed in literature the distribution of TAS2Rs in different muscle systems with a focus on the map of bitter flavored TCM which can regulate muscle contractility and related functional chemical components. We also reviewed the recently established databases of TCM chemical components and the bioinformatics software which can be used for high-throughput screening and data mining of the chemical components associated with bitter flavored TCM. All together, we aim to present a knowledge-based approach and technological platform for identification or discovery of extra-oral TAS2R agonists that can be used as novel drug agents for muscle relaxation therapies through screening and evaluation of chemical compounds used in bitter flavored TCM. [ABSTRACT FROM AUTHOR]

Sensory receptors, including olfactory receptors (ORs), taste receptors (TRs), and opsins (Opns) have recently been found in a variety of non-sensory tissues where they have distinct physiological functions. As G protein-coupled receptors (GPCRs), these proteins can serve as important chemosensors by sensing and interpreting chemical cues in the environment. We reasoned that the liver, the largest metabolic organ in the body, is primed to take advantage of some of these sensory receptors in order to sense and regulate blood content and metabolism. In this study, we report the expression of novel hepatic sensory receptors - including 7 ORs, 6 bitter TRs, and 1 Opn - identified through a systematic molecular biology screening approach. We further determined that several of these receptors are expressed within hepatocytes, the parenchymal cells of the liver. Finally, we uncovered several agonists of the previously orphaned hepatic ORs. These compounds fall under two classes: methylpyrazines and monoterpenes. In particular, the latter chemicals are plant and fungal-derived compounds with known hepatic protective effects. Collectively, this study sheds light on the chemosensory functions of the liver and unveils potentially important regulators of hepatic homeostasis., (Copyright © 2020 Kurtz, Steinberg, Betcher, Fowler and Shepard.)