Activation of specific bitter taste receptors by olive oil phenolics and secoiridoids
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ABSTRACT:
SUBMITTER: Cui M
PROVIDER: S-EPMC8595653 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca(2+) and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease.
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Project description:Beside the oral cavity, bitter taste receptors are expressed in several non-gustatory tissues. Whether extra-oral bitter taste receptors function as sensors for endogenous agonists is unknown. To address this question, we devised functional experiments combined with molecular modeling approaches to investigate human and mouse receptors using a variety of bile acids as candidate agonists. We show that five human and six mouse receptors are responsive to an array of bile acids. Moreover, their activation threshold concentrations match published data of bile acid concentrations in human body fluids, suggesting a putative physiological activation of non-gustatory bitter receptors. We conclude that these receptors could serve as sensors for endogenous bile acid levels. These results also indicate that bitter receptor evolution may not be driven solely by foodstuff or xenobiotic stimuli, but also depend on endogenous ligands. The determined bitter receptor activation profiles of bile acids now enable detailed physiological model studies.
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Project description:The T2Rs belong to a multi-gene family of G-protein-coupled receptors responsible for the detection of ingested bitter-tasting compounds. The T2Rs are conserved among mammals with the human and mouse gene families consisting of about 25 members. In the present study we address the signalling properties of human and mouse T2Rs using an in vitro reconstitution system in which both the ligands and G-proteins being assayed can be manipulated independently and quantitatively assessed. We confirm that the mT2R5, hT2R43 and hT2R47 receptors respond selectively to micromolar concentrations of cycloheximide, aristolochic acid and denatonium respectively. We also demonstrate that hT2R14 is a receptor for aristolochic acid and report the first characterization of the ligand specificities of hT2R7, which is a broadly tuned receptor responding to strychnine, quinacrine, chloroquine and papaverine. Using these defined ligand-receptor interactions, we assayed the ability of the ligand-activated T2Rs to catalyse GTP binding on divergent members of the G(alpha) family including three members of the G(alphai) subfamily (transducin, G(alphai1) and G(alphao)) as well as G(alphas) and G(alphaq). The T2Rs coupled with each of the three G(alphai) members tested. However, none of the T2Rs coupled to either G(alphas) or G(alphaq), suggesting the T2Rs signal primarily through G(alphai)-mediated signal transduction pathways. Furthermore, we observed different G-protein selectivities among the T2Rs with respect to both G(alphai) subunits and G(betagamma) dimers, suggesting that bitter taste is transduced by multiple G-proteins that may differ among the T2Rs.
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Project description:Dysregulation of thyroid hormones triiodothyronine and thyroxine (T3/T4) can impact metabolism, body composition, and development. Thus, it is critical to identify novel mechanisms that impact T3/T4 production. We found that type 2 taste receptors (TAS2Rs), which are activated by bitter-tasting compounds such as those found in many foods and pharmaceuticals, negatively regulate thyroid-stimulating hormone (TSH)-dependent Ca(2+) increases and TSH-dependent iodide efflux in thyrocytes. Immunohistochemical Tas2r-dependent reporter expression and real-time PCR analyses reveal that human and mouse thyrocytes and the Nthy-Ori 3-1 human thyrocyte line express several TAS2Rs. Five different agonists for thyrocyte-expressed TAS2Rs reduced TSH-dependent Ca(2+) release in Nthy-Ori 3-1 cells, but not basal Ca(2+) levels, in a dose-dependent manner. Ca(2+) responses were unaffected by 6-n-propylthiouracil, consistent with the expression of an unresponsive variant of its cognate receptor, TAS2R38, in these cells. TAS2R agonists also inhibited basal and TSH-dependent iodide efflux. Furthermore, a common TAS2R42 polymorphism is associated with increased serum T4 levels in a human cohort. Our findings indicate that TAS2Rs couple the detection of bitter-tasting compounds to changes in thyrocyte function and T3/T4 production. Thus, TAS2Rs may mediate a protective response to overingestion of toxic materials and could serve as new druggable targets for therapeutic treatment of hypo- or hyperthyroidism.
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Project description:Humans can recognise five basic tastes: sweet, sour, salty, bitter and umami. Sour and salty substances are linked to ion channels, while sweet, bitter and umami flavours are transmitted through receptors linked to the G protein (G protein-coupled receptors; GPCRs). There are two main types of GPCRs that transmit information about sweet, umami and bitter tastes-the Tas1r and TAS2R families. There are about 25 functional TAS2R genes coding bitter taste receptor proteins. They are found not only in the mouth and throat, but also in the intestines, brain, bladder and lower and upper respiratory tract. The determination of their purpose in these locations has become an inspiration for much research. Their presence has also been confirmed in breast cancer cells, ovarian cancer cells and neuroblastoma, revealing a promising new oncological marker. Polymorphisms of TAS2R38 have been proven to have an influence on the course of chronic rhinosinusitis and upper airway defensive mechanisms. TAS2R receptors mediate the bronchodilatory effect in human airway smooth muscle, which may lead to the creation of another medicine group used in asthma or chronic obstructive pulmonary disease. The discovery that functionally compromised TAS2R receptors negatively impact glucose homeostasis has produced a new area of diabetes research. In this article, we would like to focus on what facts have been already established in the matter of extraoral TAS2R receptors in humans.
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Project description:The composition of menus and the sequence of foodstuffs consumed during a meal underlies elaborate rules. However, the molecular foundations for the observed taste- and pleasure-raising effects of complex menus are obscure. The molecular identification and characterization of taste receptors can help to gain insight into the complex interrelationships of food items and beverages during meals. In our study, we quantified important bitter compounds in chicory and chicory-based surrogate coffee and used them to identify responsive bitter taste receptors. The two receptors, TAS2R43 and TAS2R46, are exquisitely sensitive to lactucin, lactucopicrin, and 11β,13-dihydrolactucin. Sensory testing demonstrated a profound influence of the sequence of consumption of chicory, surrogate coffee, and roasted coffee on the perceived bitterness by human volunteers. These findings pave the way for a molecular understanding of some of the mixture effects underlying empirical meal compositions.
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Project description:Bitterness is one of the five basic tastes, and sensitivity to bitterness is important in that it enables animals to avoid harmful and toxic substances. In humans, taste sensitivity decreases with age, although the extent of loss varies depending on the taste quality. In chickens (Gallus gallus domesticus), baby chicks have been found to be more sensitive to salt and sour taste qualities than adults. In this study, therefore, we investigated the growth-associated changes in bitter taste sensitivity in chicks. We examined the behavioral perceptions toward the bitter compounds chloramphenicol and andrographolide in chicks at three different growth stages. Then, we measured the relative expression of the functional bitter taste receptors in the chick palate. In behavioral drinking tests, the 0-1-week-old chicks consumed a significantly lower amount of bitter solutions than water, whereas the 8-9-week-old chicks showed lower avoidance of the bitter solutions than the 0-1-week-old and 4-5-week-old chicks. Real-time PCR assay showed that the 0-1-week-old chicks had significantly higher expression of one of the functional bitter taste receptors in the palate than that in the older chicks. These results suggest that baby chicks are more sensitive to bitterness than older chicks. These findings may be useful in the production of new feedstuff for chicks according to their growth stages.
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Project description:Bitter compounds elicit an aversive response. In Drosophila, bitter-sensitive taste neurons coexpress many members of the Gr family of taste receptors. However, the molecular logic of bitter signaling is unknown. We used an in vivo expression approach to analyze the logic of bitter taste signaling. Ectopic or overexpression of bitter Grs increased endogenous responses or conferred novel responses. Surprisingly, expression of Grs also suppressed many endogenous bitter responses. Conversely, deletion of an endogenous Gr led to novel responses. Expression of individual Grs conferred strikingly different effects in different neurons. The results support a model in which bitter Grs interact, exhibiting competition, inhibition, or activation. The results have broad implications for the problem of how taste systems evolve to detect new environmental dangers.
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Project description: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.
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Project description:Bitter taste-sensing type 2 receptors (TAS2Rs or T2Rs), belonging to the subgroup of family A G-protein coupled receptors (GPCRs), are of crucial importance in the perception of bitterness. Although in the first instance, TAS2Rs were considered to be exclusively distributed in the apical microvilli of taste bud cells, numerous studies have detected these sensory receptor proteins in several extra-oral tissues, such as in pancreatic or ovarian tissues, as well as in their corresponding malignancies. Critical points of extra-oral TAS2Rs biology, such as their structure, roles, signaling transduction pathways, extensive mutational polymorphism, and molecular evolution, have been currently broadly studied. The TAS2R cascade, for instance, has been recently considered to be a pivotal modulator of a number of (patho)physiological processes, including adipogenesis or carcinogenesis. The latest advances in taste receptor biology further raise the possibility of utilizing TAS2Rs as a therapeutic target or as an informative index to predict treatment responses in various disorders. Thus, the focus of this review is to provide an update on the expression and molecular basis of TAS2Rs functions in distinct extra-oral tissues in health and disease. We shall also discuss the therapeutic potential of novel TAS2Rs targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles.
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