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Bitter taste receptors (TAS2Rs) are not only expressed in the oral cavity but also in skin. Extraoral TAS2Rs are thought to be involved in non‐taste perception and tissue‐specific functions. Keratinocytes that express TAS2Rs in the skin provide a first‐line defense against external threats. However, the functional roles of these receptors in host defense remain unclear. Here, we demonstrated the sensory role of intracellularly located TAS2Rs against toxic substances in keratinocytes. Although many G protein‐coupled receptors elicit signals from the surface, TAS2Rs were found to localize intracellularly, possibly to the ER, in human keratinocytes and HaCaT cells. TAS2R38, one of the TAS2R members, activated the Gα12/13/RhoA/ROCK/p38 MAP kinase/NF‐κB pathway upon stimulation by phenylthiocarbamide (PTC), an agonist for this receptor, leading to the production of ABC transporters, such as ABCB1, in these cells. Notably, treatment with bitter compounds, such as PTC and saccharin, induced the upregulation of ABCB1 in HaCaT cells. Mechanistically, intracellular TAS2R38 and its downstream signaling Gα12/13/RhoA/ROCK/p38 MAP kinase/NF‐κB pathway were identified to be responsible for the above effect. Pretreatment with PTC prevented the accumulation of rhodamine 123 because of its excretion via ABCB1. Furthermore, pretreatment with PTC or saccharin counteracted the effect of the toxic compound, diphenhydramine, and pretreated HaCaT cells were found to proliferate faster than untreated cells. This anti‐toxic effect was suppressed by treatment with verapamil, an ABCB1 inhibitor, indicating that enhanced ABCB1 helps clear toxic substances. Altogether, harmless activators of TAS2Rs may be promising drugs that enhance the excretion of toxic substances from the human skin. [ABSTRACT FROM AUTHOR]

Type 2 taste receptors (TAS2Rs), traditionally known for their role in bitter taste perception, are present in diverse reproductive tissues of both sexes. This review explores our current understanding of TAS2R functions with a particular focus on reproductive health. In males, TAS2Rs are believed to play potential roles in processes such as sperm chemotaxis and male fertility. Genetic insights from mouse models and human polymorphism studies provide some evidence for their contribution to male infertility. In female reproduction, it is speculated that TAS2Rs influence the ovarian milieu, shaping the functions of granulosa and cumulus cells and their interactions with oocytes. In the uterus, TAS2Rs contribute to uterine relaxation and hold potential as therapeutic targets for preventing preterm birth. In the placenta, they are proposed to function as vigilant sentinels, responding to infection and potentially modulating mechanisms of fetal protection. In the cervix and vagina, their analogous functions to those in other extraoral tissues suggest a potential role in infection defense. In addition, TAS2Rs exhibit altered expression patterns that profoundly affect cancer cell proliferation and apoptosis in reproductive cancers. Notably, TAS2R agonists show promise in inducing apoptosis and overcoming chemoresistance in these malignancies. Despite these advances, challenges remain, including a lack of genetic and functional studies. The application of techniques such as single‐cell RNA sequencing and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR‐associated endonuclease 9 gene editing could provide deeper insights into TAS2Rs in reproduction, paving the way for novel therapeutic strategies for reproductive disorders. [ABSTRACT FROM AUTHOR]

Citrus is an important source of flavonoids in our daily diet. Citrus flavonoids have antioxidant, anticancer, anti‐inflammatory, and cardiovascular disease prevention functions. Studies have shown that some pharmaceutical values of flavonoids may be related to their binding to bitter taste receptors, thus activating downstream signal transduction pathways; however, the underlying mechanism has not been systematically elucidated. In this paper, the biosynthesis pathway and the absorption and metabolism of citrus flavonoids were briefly reviewed, and the relationship between flavonoid structure and bitter taste intensity was investigated. In addition, the pharmacological effects of bitter flavonoids and the activation of bitter taste receptors in combating various diseases were discussed. This review provides an important basis for the targeted design of citrus flavonoid structures to make them more biologically active and more attractive as powerful drugs for the effective treatment of chronic diseases such as obesity, asthma, and neurological diseases. [ABSTRACT FROM AUTHOR]

Objectives: Chronic rhinosinusitis (CRS) is a major hallmark of primary ciliary dyskinesia (PCD). We investigated the possible correlation between some severity markers of CRS and several clinical features of the disease. We further studied the bitter taste receptor TAS2R38 polymorphisms to identify the genotypes associated with more severe disease. Methods: We included 39 adult PCD patients with (CRSwNP) and without nasal polyposis (CRSsNP); a sample for nasal cytology was obtained and clinical cytological grading (CCG) was determined. The SNOT‐22 and Lund‐Mackay scores were recorded. A sample of DNA was extracted from peripheral blood to investigate TAS2R38 polymorphisms. Results: CRSwNP patients had features of more severe disease: indeed, they had statistically significantly higher frequency of previous sinus surgery, higher SNOT‐22, LM scores, and CCG than CRSsNP patients. Upon genotyping of TAS2R38 polymorphisms, we observed that the AVI–AVI genotype, associated to homozygous nonfunctional bitter TAS2R38 receptor, was more prevalent among CRSwNP (100%) than in CRSsNP patients (0%); furthermore, AVI–AVI subjects showed statistically significantly worse SNOT‐22 and CCG scores than PAV–PAV and PAV–AVI subjects. The group of AVI–AVI patients also had more frequent respiratory exacerbations, Gram‐negative infections, and Pseudomonas aeruginosa colonization than PAV–PAV and PAV–AVI patients. Conclusion: Our findings indicate for the first time that PCD patients with CRSwNP display a more severe disease than those with CRSsNP. Genotyping of TAS2R38 polymorphisms demonstrated that in PCD patients, the AVI–AVI genotype is strikingly more prevalent among CRSwNP than in CRSsNP, while the PAV–PAV genotype might be protective against Gram‐negative infections and respiratory exacerbations. Level of Evidence: 3 Laryngoscope, 133:248–254, 2023 [ABSTRACT FROM AUTHOR]

The chemical senses of olfaction and taste are well developed in fish and play a vital role in its various activities such as navigation, mate recognition, and food detection. The small teleost fish Astyanax mexicanus consists of interfertile river‐dwelling and cave‐dwelling populations, referred to as "surface fish" and "cavefish" respectively. An important anatomical feature of cavefish is the lack of eyes leading them to be referred to as blind fish and suggesting an enhanced functional role for other senses such as taste. In this study, we characterize the expression of bitter taste receptors (T2Rs or Tas2Rs) in A. mexicanus and investigate their functionality in a heterologous expression system. The genome database of A. mexicanus (ensemble and NCBI) showed 7 Tas2Rs, among these Tas2R1, Tas2R3, Tas2R4, and Tas2R114 are well characterized in humans and mice but not in A. mexicanus. Therefore, the 4 Tas2Rs were selected for further analysis and their expression in A. mexicanus was confirmed by in situ hybridization and RT‐PCR in early developmental stages. These Tas2Rs are expressed in various oral and extraoral organs (liver, fins, jaws, and gills) in A. mexicanus, and Tas2R1 has maximum expression and is localized throughout the fish body. Using the heterologous expression of A. mexicanus T2Rs in HEK293T cells coupled with cell‐based calcium mobilization assays, we show that A. mexicanus T2Rs are activated by commonly used fish food and known bitter agonists, including quinine. This study provides novel insights into the extraoral expression of T2Rs in A. mexicanus and suggests their importance in extraoral food detection. [ABSTRACT FROM AUTHOR]

Preclinical studies in animal models of obesity and inflammation have shown that oral administration of ARD‐101, a potential TAS2R agonist, reduced food intake and body weight and downregulated inflammatory cytokines. We present results from a first‐in‐human phase 1 randomized, placebo‐controlled trial that evaluated safety, pharmacokinetics, and pharmacodynamics of single or multiple ascending doses of oral ARD‐101 (40, 100, and 240 mg) in healthy adults. A total of 43 subjects were randomly assigned and dosed to ARD‐101 or placebo with 42 subjects completing the study treatment. ARD‐101 was found to be >99% restricted to the gut with minimal systemic exposure, demonstrated a favorable safety profile, and was well tolerated at all dose levels. Blood samples taken 1 hour after administration showed that subjects dosed with 240 mg of ARD‐101 had elevated circulating levels of several gut peptide hormones. It is postulated that ARD‐101 activates enteroendocrine cells to achieve its effects regulating metabolism and inflammation. The phase 1 clinical results demonstrated safety of ARD‐101 and indicated activation of gut peptide hormone release in healthy adults. Further clinical trials will evaluate ARD‐101 in patients with metabolic and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the presence of bitter taste receptors (T2Rs) in the middle ear and to examine their relationship with chronic ear infections. Study Design: Cross-sectional study. Setting: Tertiary care hospital. Methods: This study enrolled 84 patients being evaluated for otologic surgery: 40 for chronic otitis media (COM) and 44 for other surgical procedures (controls). We collected a small piece of mucosa from 14 patients for mRNA analysis and from 23 patients for immunohistochemistry. A total of 55 patients underwent a double-blind taste test to gauge sensitivity to phenylthiocarbamide, denatonium, quinine, sucrose, and sodium chloride; 47 patients gave a salivary sample for single-nucleotide polymorphism analysis of rs1376251 (TAS2R50) and rs1726866 (TAS2R38). Results: Bitter taste receptors were found in all samples, but the repertoire varied among patients. T2R50 was the most consistently identified receptor by mRNA analysis. Its rs1376251 allele was related to susceptibility to COM but not the expression pattern of T2R50. Ratings of bitterness intensity of phenylthiocarbamide, a ligand for T2R38, differed significantly between the COM and control groups. Conclusion: T2Rs were found within the middle ear of every patient sampled; the rs1376251 allele of TAS2R50 appears to be related to chronic ear infections. These receptors are an intriguing target for future research and possible drug targeting. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP), and aspirin‐exacerbated respiratory disease (AERD) have varying levels of inflammation and disease severity. Solitary chemosensory cells (SCCs) are enriched in nasal polyps, are the primary source of interleukin 25 (IL‐25) in upper airways, leading to type 2 inflammation, and are activated by bitter‐tasting denatonium benzoate (DB). Thus, we sought to evaluate DB taste perception at a range of concentrations in order to identify 1 that most differentiates CRS subgroups from controls. Methods: CRSsNP (n = 25), CRSwNP (n = 26), and AERD (n = 27) patients as well as controls (n = 25) tasted 6 DB concentrations in a fixed, random order, rating on a category scale of 0 (no intensity) to 12 (extremely intense). Sinonasal epithelial cultures were treated with and without denatonium and analyzed for IL‐25 via flow cytometry. Results: CRSsNP patients rated DB as significantly less intense than did controls at all concentrations: 5.62 × 10–9M, 1.00 × 10–8M, 1.78 × 10–8M, 3.16 × 10–8M, 5.62 × 10–8M, and 1.00 × 10–7M (all p < 0.0083). CRSwNP patients did not show significant differences from controls. AERD patients rated DB as significantly more intense than did controls at concentrations of 1.00 × 10–8M and 3.16 × 10–8M (p < 0.0083). In vitro data demonstrated significant increase in IL‐25–positive cells after denatonium stimulation (n = 5), compared to control (n = 5) (p = 0.012). Conclusion: Our findings link in vitro DB stimulation of sinonasal tissue with increased IL‐25 and show differential DB taste perception in CRS subgroups relative to the control group, with CRSsNP being hyposensitive and AERD being hypersensitive. We propose a concentration of 3.16 × 10–8M for future study of clinical utility. [ABSTRACT FROM AUTHOR]

Background: Bitter and sweet taste receptors are present in the human upper airway, where they have roles in innate immunity. Previous studies have shown that 1 of the 25 bitter receptors, TAS2R38, responds to specific bacterial signaling molecules and evokes 1 type of a defense response in the upper airway, whereas ligands of sweet receptors suppress other types of defense responses. Methods: We examined whether other bitter taste receptors might also be involved in innate immunity by using sensory responses to bitter compounds that are not ligands of TAS2R38 (quinine and denatonium benzoate) to assess the sensitivity of other bitter receptors in chronic rhinosinusitis (CRS) patients. CRS patients with (n = 426) and without (n = 226) nasal polyps and controls (n = 356) rated the intensity of quinine, denatonium benzoate, phenylthiocarbamide (PTC; a ligand for TAS2R38), sucrose, and salt. Results: CRS patients rated the bitter compounds denatonium benzoate and quinine as less intense and sucrose as more intense than did controls (false discovery rate [FDR] <0.05) and CRS patients and controls did not differ in their ratings of salt (FDR >0.05). PTC bitter taste intensity differed between patient and control groups but were less marked than those previously reported. Though differences were statistically significant, overall effect sizes were small. Conclusion: CRS patients report bitter stimuli as less intense but sweet stimuli as more intense than do control subjects. We speculate that taste responses may reflect the competence of sinonasal innate immunity mediated by taste receptor function, and thus a taste test may have potential for clinical utility in CRS patients. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome‒associated coronavirus‐2 (SARS‐CoV‐2) has been identified as the pathogen causing the outbreak of coronavirus disease‐2019 (COVID‐19) commencing in Wuhan, China, in December 2019. Multiple reports have shown subjective loss of taste and smell as an early and hallmark symptom for COVID‐19. Methods: A retrospective study was performed in our clinical practice during July 2020 on patients positive for SARS‐CoV‐2 via polymerase chain reaction. All patients were categorized into 3 groups (supertasters, tasters, and nontasters) via taste sensitivity to phenylthiocarbamide, thiourea, and sodium benzoate with taste strip testing. The results of the taste strip tests were correlated with clinical course. Results: A total of 100 patients (mean, 51 [range, 24‐82] years of age; 44 [44%] women) were assessed. We found that 21 of 100 (21%) were nontasters, 79 of 100 (79%) were tasters, and 0 of 100 (0%) were supertasters (p < 0.001). Twenty‐one of 21 (100%) (p < 0.001) of the patients requiring inpatient admission were classified as nontasters. All 79 (100%) (p < 0.001) of the patients who displayed mild to moderate symptoms not requiring admission were classified as tasters. Conclusion: Our results show objective data that taste disturbance, specifically global loss of taste, appears to correlate with the clinical course specific to each individual, because 100% of the patients requiring inpatient admission were classified as nontasters. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2012) 122, 537-544. Abstract The human bitter taste receptors (T2Rs) belong to the G-protein coupled receptor (GPCR) superfamily. T2Rs share little homology with the large subfamily of Class A G-protein coupled receptors, and their mechanisms of activation are poorly understood. Guided by biochemical and molecular approaches, we identified two conserved amino acids Gly281.46 and Ser2857.47 present on transmembrane (TM) helices, TM1 and TM7, which might play important roles in T2R activation. Previously, it was shown that naturally occurring Gly511.46 mutations in the dim light receptor, rhodopsin, cause autosomal dominant retinitis pigmentosa, with the mutants severely defective in signal transduction. We mutated Gly281.46 and Ser2857.47 in T2R4 to G28A, G28L, S285A, S285T, and S285P, and carried out pharmacological characterization of the mutants. No major changes in signaling were observed upon mutation of Gly281.46 in T2R4. Interestingly, S285A mutant displayed agonist-independent activity (approximately threefold over basal wild-type T2R4 or S285T or S285P). We propose that Ser2857.47 stabilizes the inactive state of T2R4 by a network of hydrogen-bonds connecting important residues on TM1-TM2-TM7. We compare and contrast this hydrogen-bond network with that present in rhodopsin. Thus far, S285A is the first constitutively active T2R mutant reported, and gives novel insights into T2R activation. [ABSTRACT FROM AUTHOR]