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Heterotrimeric G protein-coupled receptors (GPCRs) comprise the largest receptor family in mammals and are responsible for the regulation of most physiological functions. Besides mediating the sensory modalities of olfaction and vision, GPCRs also transduce signals for three basic taste qualities of sweet, umami (savory taste), and bitter, as well as the flavor sensation kokumi. Taste GPCRs reside in specialised taste receptor cells (TRCs) within taste buds. Type I taste GPCRs (TAS1R) form heterodimeric complexes that function as sweet (TAS1R2/TAS1R3) or umami (TAS1R1/TAS1R3) taste receptors, whereas Type II are monomeric bitter taste receptors or kokumi/calcium-sensing receptors. Sweet, umami and kokumi receptors share structural similarities in containing multiple agonist binding sites with pronounced selectivity while most bitter receptors contain a single binding site that is broadly tuned to a diverse array of bitter ligands in a non-selective manner. Tastant binding to the receptor activates downstream secondary messenger pathways leading to depolarization and increased intracellular calcium in TRCs, that in turn innervate the gustatory cortex in the brain. Despite recent advances in our understanding of the relationship between agonist binding and the conformational changes required for receptor activation, several major challenges and questions remain in taste GPCR biology that are discussed in the present review. In recent years, intensive integrative approaches combining heterologous expression, mutagenesis and homology modeling have together provided insight regarding agonist binding site locations and molecular mechanisms of orthosteric and allosteric modulation. In addition, studies based on transgenic mice, utilizing either global or conditional knock out strategies have provided insights to taste receptor signal transduction mechanisms and their roles in physiology. However, the need for more functional studies in a physiological context is apparent and would be enhanced by a crystallized structure of taste receptors for a more complete picture of their pharmacological mechanisms.

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.

The vertebrate sense of taste allows rapid assessment of the nutritional quality and potential presence of harmful substances prior to ingestion. Among the five basic taste qualities, salty, sour, sweet, umami, and bitter, bitterness is associated with the presence of putative toxic substances and elicits rejection behaviors in a wide range of animals including humans. However, not all bitter substances are harmful, some are thought to be health-beneficial and nutritious. Among those compound classes that elicit a bitter taste although being non-toxic and partly even essential for humans are bitter peptides and l -amino acids. Using functional heterologous expression assays, we observed that the 5 dominant human bitter taste receptors responsive to bitter peptides and amino acids are activated by bile acids, which are notorious for their extreme bitterness. We further demonstrate that the cross-reactivity of bitter taste receptors for these two different compound classes is evolutionary conserved and can be traced back to the amphibian lineage. Moreover, we show that the cross-detection by some receptors relies on “structural mimicry” between the very bitter peptide l -Trp-Trp-Trp and bile acids, whereas other receptors exhibit a phylogenetic conservation of this trait. As some bile acid-sensitive bitter taste receptor genes fulfill dual-roles in gustatory and non-gustatory systems, we suggest that the phylogenetic conservation of the rather surprising cross-detection of the two substance classes could rely on a gene-sharing-like mechanism in which the non-gustatory function accounts for the bitter taste response to amino acids and peptides.

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.

Water in the external environment is detected by acid-sensing taste receptor cells via a carbonic anhydrase 4-mediated pH change.

The authors find that mammalian acid-sensing taste receptor cells, previously shown to be putative sour taste sensors, also mediate responses to water. Optogenetic activation of this population of cells in thirsty mice induced robust drinking response in the absence of water. This study shows that acid-sensing TRCs contribute to the detection of water in the oral cavity. Initiation of drinking behavior relies on both internal state and peripheral water detection. While central neural circuits regulating thirst have been well studied, it is still unclear how mammals recognize external water. Here we show that acid-sensing taste receptor cells (TRCs) that were previously suggested as the sour taste sensors also mediate taste responses to water. Genetic silencing of these TRCs abolished water-evoked responses in taste nerves. Optogenetic self-stimulation of acid-sensing TRCs in thirsty animals induced robust drinking responses toward light even without water. This behavior was only observed when animals were water-deprived but not under food- or salt-depleted conditions, indicating that the hedonic value of water-evoked responses is highly internal-state dependent. Conversely, thirsty animals lacking functional acid-sensing TRCs showed compromised discrimination between water and nonaqueous fluids. Taken together, this study revealed a function of mammalian acid-sensing TRCs that provide a cue for external water.

Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor, TAS2R43, and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine’s bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bittermasking compounds could be potentially useful therapeutics to regulate gastric pH.

Human bitter taste receptors (TAS2Rs) are a subfamily of 25 G protein-coupled receptors that mediate bitter taste perception. TAS2R14 is the most broadly tuned bitter taste receptor, recognizing a range of chemically diverse agonists with micromolar-range potency. The receptor is expressed in several extra-oral tissues and is suggested to have physiological roles related to innate immune responses, male fertility, and cancer. Higher potency ligands are needed to investigate TAS2R14 function and to modulate it for future clinical applications. Here, a structure-based modeling approach is described for the design of TAS2R14 agonists beginning from flufenamic acid, an approved non-steroidal anti-inflammatory analgesic that activates TAS2R14 at sub-micromolar concentrations. Structure-based molecular modeling was integrated with experimental data to design new TAS2R14 agonists. Subsequent chemical synthesis and in vitro profiling resulted in new TAS2R14 agonists with improved potency compared to the lead. The integrated approach provides a validated and refined structural model of ligand–TAS2R14 interactions and a general framework for structure-based discovery in the absence of closely related experimental structures.

The sweet taste of saccharides, such as sucrose and glucose, and other sweeteners is known to result from activation of the TAS1R2/R3 receptor expressed in taste receptor cells (TRCs) of the taste bud. Recent reports have suggested the existence of an additional sweet taste signaling pathway for metabolizable saccharides that is dependent on the activity of glucose transporters, especially SGLT1, also expressed in TRCs. We have investigated the potential contribution of SGLT1 to glucose taste signaling in humans. Concentration-response analysis of glucose mediated changes in membrane potential measured in Chinese hamster ovary (CHO) cells transiently expressing the human SGLT1 (hSGLT1) yielded an EC50 value of 452 μM. The SGLT inhibitor phlorizin inhibited the membrane potential response to 10 mM glucose with an IC50 of 3.5 μM. In contrast, EC50 values of 127 and 132 mM were obtained from concentration-response analysis of glucose taste in vehicles of water or 20 mM NaCl, respectively, by rapid throughput taste discrimination with human subjects. Lactisole, an antagonist of TAS1R2/R3, at a concentration of 1 mM completely inhibited taste responses to glucose concentrations of 250 mM and below. Phlorizin (0.2 mM) and the high potency SGLT1-selective inhibitor mizagliflozin (10 μM) failed to inhibit glucose taste detection measured at peri-threshold concentrations in the rapid throughput taste discrimination assay. A Yes/No experiment using the taste discrimination assay revealed that 0.2 mM phlorizin was discriminable from water for some subjects. Taken together the results indicate that agonist activation of TAS1R2/R3 is sufficient to account for all glucose taste without contribution by an alternative SGLT-mediated signaling pathway. Furthermore, the taste of phlorizin could be a confounding variable for studies evaluating a role for SGLTs in taste.

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).