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Oral cancer is a leading cause of cancer-related deaths and significantly affects the quality of life of patients. However, many of its mechanisms remain unclear, and its treatment needs improvement. The G-protein-coupled receptor taste receptor type 2 member 14 (T2R14 or TAS2R14) is expressed in various cancer types. However, few studies have investigated its roles in oral cancer, and its effects on oral cancer cell proliferation and growth are unknown. This study aimed to examine T2R14’s impact on proliferation and cell population growth (CPG) of oral cancer cells. TAS2R14 gene knockout was performed, and cell numbers, cell viability, and colony formation were measured. This study showed that TAS2R14 knockout in oral cancer cells significantly decreased calcium mobilization, increased cell numbers, colony formation, the proliferation marker proliferating cell nuclear antigen, and the phosphorylation of mechanistic target of rapamycin, but did not affect cell viability. These observations are consistent with the clinical data that higher TAS2R14 mRNA expression is associated with better survival of patients with oral cancer. Therefore, T2R14 downregulation increased oral cancer CPG, suggesting a tumor-suppressor-like role. The study’s findings could improve our understanding of T2R14 mechanisms and help develop strategies to advance oral cancer treatment by targeting T2R14.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors 1 . Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants 2 , 3 , 4 , 5 – 6 , although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with G gust (also known as gustducin) and G i1 . Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of G gust and G i1 . Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants. Cryo-electron microscopy structures of the type 2 taste receptor TAS2R14 in complex with Ggust and Gi1 identify cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator and agonist.

Humans can perceive five canonical tastes: salty, sour, umami, sweet, and bitter. These tastes are transmitted through the activation of ion channels and receptors. Bitter taste receptors (Taste Family 2 Receptors; T2Rs) are a sub-family of 25 G-protein coupled receptor (GPCR) isoforms that were first identified in type II taste bud cells. T2Rs are activated by a broad array of bitter agonists, which cause an increase in intracellular calcium (Ca 2+ ) and a decrease in cyclic adenosine 3’,5’-monophosphate (cAMP). Interestingly, T2Rs are expressed beyond the oral cavity, where they play diverse non-taste roles in cell physiology and disease. Here, we summarize the literature that explores the role of T2Rs in apoptosis. Activation of T2Rs with bitter agonists induces apoptosis in several cancers, the airway epithelia, smooth muscle, and more. In many of these tissues, T2R activation causes mitochondrial Ca 2+ overload, a main driver of apoptosis. This response may be a result of T2R cellular localization, nuclear Ca 2+ mobilization and/or a remnant of the established immunological roles of T2Rs in other cell types. T2R-induced apoptosis could be pharmacologically leveraged to treat diseases of altered cellular proliferation. Future work must explore additional extra-oral T2R-expressing tissues for apoptotic responses, develop methods for in-vivo studies, and discover high affinity bitter agonists for clinical application.

TAS2Rs are a family of G protein-coupled receptors that function as bitter taste receptors in vertebrates. Mammalian TAS2Rs have historically garnered the most attention, leading to our understanding of their roles in taste perception relevant to human physiology and behaviors. However, the evolution and functional implications of TAS2Rs in other vertebrate lineages remain less explored. Here, we identify 9,291 TAS2Rs from 661 vertebrate genomes. Large-scale phylogenomic analyses reveal that frogs and salamanders contain unusually high TAS2R gene content, in stark contrast to other vertebrate lineages. In most species, TAS2R genes are found in clusters; compared to other vertebrates, amphibians have additional clusters and more genes per cluster. We find that vertebrate TAS2Rs have few one-to-one orthologs between closely related species, although total TAS2R count is stable in most lineages. Interestingly, TAS2R count is proportional to the receptors expressed solely in extra-oral tissues. In vitro receptor activity assays uncover that many amphibian TAS2Rs function as tissue-specific chemosensors to detect ecologically important xenobiotics.

Bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs) expressed orally and extraorally, elicit signaling in response to a large set of tastants. Among 25 functional TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of chemically diverse ligands. Here we present the cryo–electron microscopy (cryo-EM) structure of the human TAS2R14 in complex with its signaling partner gustducin, and bound to flufenamic acid (FFA), a clinically approved nonsteroidal anti-inflammatory drug. The structure reveals an unusual binding mode, where two copies of FFA are bound at distinct pockets: one at the canonical receptor site within the trans-membrane bundle, and the other in the intracellular facet, bridging the receptor with gustducin. Together with a pocket-specific BRET-based ligand binding assay, these results illuminate bitter taste signaling and provide tools for a site-targeted compound design. Bitter taste receptors (TAS2Rs) are a subfamily of G-protein coupled receptors (GPCRs). Here, the authors report a cryo-EM structure of the human TAS2R14 in complex with its signaling partner gustducin, and bound to an anti-inflammatory drug flufenamic acid (FFA).

Taste is important in the selection of food and is orchestrated by a group of distinct receptors, the taste G protein-coupled receptors (GPCRs). Taste 1 receptors (Tas1rs in mice and TAS1Rs in humans; also known as T1Rs) detect sweet and umami tastes, and taste 2 receptors (Tas2rs in mice and TAS2Rs in humans; also known as T2Rs) detect bitterness. These receptors are also expressed in extraoral sites, including the gastrointestinal mucosa. Tas2rs/TAS2Rs have gained interest as potential targets to prevent or treat metabolic disorders. These bitter taste receptors are expressed in functionally distinct types of gastrointestinal mucosal cells, including enteroendocrine cells, which, upon stimulation, increase intracellular Ca 2+ and release signalling molecules that regulate gut chemosensory processes critical for digestion and absorption of nutrients, for neutralization and expulsion of harmful substances, and for metabolic regulation. Expression of Tas2rs/TAS2Rs in gut mucosa is upregulated by high-fat diets, and intraluminal bitter ‘tastants’ affect gastrointestinal functions and ingestive behaviour through local and gut–brain axis signalling. Tas2rs/TAS2Rs are also found in Paneth and goblet cells, which release antimicrobial peptides and glycoproteins, and in tuft cells, which trigger type 2 immune response against parasites, thus providing a direct line of defence against pathogens. This Review will focus on gut Tas2r/TAS2R distribution, signalling and regulation in enteroendocrine cells, supporting their role as chemosensors of luminal content that serve distinct functions as regulators of body homeostasis and immune response. Type 2 taste receptors (Tas2rs in mice and TAS2Rs in humans) detect bitter stimuli and are present in both the oral cavity and extraoral sites. In this Review, the authors discuss Tas2rs/TAS2Rs in the gastrointestinal enteroendocrine system and how they could be potential targets to prevent or treat metabolic disorders. Key points Bitter taste receptors (type 2 taste receptors; Tas2rs/TAS2Rs) are G protein-coupled receptors (GPCRs) that detect bitter, potentially harmful substances, although bitterness does not predict toxicity and is not always aversive. Functional genes exist for approximately 25 human bitter taste receptors (TAS2Rs) and ~36 rodent bitter taste receptors (Tas2rs); these genes detect a large number of natural and synthetic, structurally divergent compounds. Tas2rs/TAS2Rs differ in their tuning broadness: some sense just a few or single ligands, and others are broadly tuned to recognize multiple tastants many of which activate multiple receptors. Human TAS2Rs and mouse Tas2rs are found in many extraoral locations, where they serve various extragustatory functions, depending on the site of expression. Multiple TAS2Rs/Tas2rs have been identified in the human and rodent gastrointestinal tract, where they are localized to distinct cell types, including enteroendocrine, goblet, Paneth and tuft cells. Gut Tas2rs/TAS2Rs have been proposed as sensors of bile acids, bacteria, bacterial products, parasites and plant alkaloids; they might also serve as regulators of gut homeostasis in conditions of dysbiosis associated with obesity and metabolic syndrome and as defence mechanisms against infection.

Cilia are microscopic projections that extend from eukaryotic cells. There are two general types of cilia; primary cilia serve as sensory organelles, whereas motile cilia exert mechanical force. The motile cilia emerging from human airway epithelial cells propel harmful inhaled material out of the lung. We found that these cells express sensory bitter taste receptors, which localized on motile cilia. Bitter compounds increased the intracellular calcium ion concentration and stimulated ciliary beat frequency. Thus, airway epithelia contain a cell-autonomous system in which motile cilia both sense noxious substances entering airways and initiate a defensive mechanical mechanism to eliminate the offending compound. Hence, like primary cilia, classical motile cilia also contain sensors to detect the external environment.

Ritonavir is a protease inhibitor used in combination with other antiretroviral drugs to treat HIV, especially in children. It enhances the effectiveness of these drugs by inhibiting the cytochrome P450-3A4 enzyme, thereby increasing their bioavailability. Ritonavir is also being investigated for cancer treatment due to its mechanism of action. However, its intense bitterness, particularly in liquid formulations, can be intolerable for some children. This bitterness is attributed to its activation of bitter taste receptors, including TAS2R14 (also named T2R14), as demonstrated in our previous study. In this study, we utilized molecular modeling, site-directed mutagenesis, and cell-based calcium mobilization assays to characterize the key residues involved in TAS2R14 activation by ritonavir. Eight critical residues for ritonavir interacting with the receptor were discovered. The results indicate two potential binding sites for ritonavir in TAS2R14 receptor, including orthosteric and allosteric sites. These findings can be useful for developing bitter blockers targeting TAS2R14 to eliminate or reduce the bitter taste of ritonavir.

The bitter taste receptor type 5 (TAS2R5) is expressed on multiple cell types and appears to be a suitable target for novel agonist treatments across multiple therapeutic areas. Like most G protein coupled receptors (GPCRs), TAS2R5 undergoes functional desensitization with prolonged agonist exposure which could limit effectiveness. The net loss of cellular receptors (termed downregulation) is a prominent mechanism of long-term desensitization; we screened 13 agonists for downregulation of receptor protein in TAS2R5-transfected HEK-293T and airway smooth muscle cells in culture, searching for pathway selectivity favoring G protein coupling over downregulation. The benchmark agonist 1,10-phenanthroline (denoted T5-1) evoked as much as 75% downregulation of TAS2R5 protein expression with 18-24 hrs of agonist exposure, while an analogue of T5-1 (denoted T5-12) caused a 2-3 fold increase in expression. Functionally, T5-1 and T5-12 were found to be full agonists when measuring [Ca 2+ ] i or ERK1/2 stimulation. The T5-12 phenotype was found to be due to agonist-induced stabilization of the receptor confining it to the cell membrane with subsequent failure to undergo internalization and receptor degradation. This occurred despite normal (referenced to T5-1) GRK-mediated receptor phosphorylation and β-arrestin recruitment by T5-12. Consistent with the lack of downregulation, T5-12 evoked much less functional desensitization of the [Ca 2+ ] i (43% vs 78%) and ERK1/2 (64% vs > 95%) responses compared to T5-1, respectively. We conclude that TAS2R5 pathway signaling is malleable to a more favorable therapeutic profile by agonist-receptor interactions that preserve primary signaling and minimizes desensitization.

The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes.