bitter taste receptors
J. Infect. TAS2Rs have been confirmed at transcript level using genome-wide expression analyses of isolated blood leukocytes. (2010). 17:54. doi: 10.1186/s12881-016-0321-3, Gerthoffer, W. T., Solway, J., and Camoretti-Mercado, B. Received: 02 May 2019; Accepted: 24 June 2019;Published: 16 July 2019. Exp. The number of compounds that trigger bitter taste sensation are significantly in excess to the number of TAS2R gene-encoded proteins, thus emphasizing promiscuity in receptor activation (Behrens et al., 2004; Di Pizio and Niv, 2015). Airway remodeling in asthma: new mechanisms and potential for pharmacological intervention. Enteroendocrine cells: a site of ‘taste’ in gastrointestinal chemosensing. By continuing you agree to the use of cookies. doi: 10.12688/f1000research.14581.1, Nguyen, L. P., Al-Sawalha, N. A., Parra, S., Pokkunuri, I., Omoluabi, O., Okulate, A. Int. doi: 10.1126/science.6691151. Inhibition of neutrophil recruitment by TAS2R agonism could potentially benefit in cases of neutrophilic severe asthma or in mitigating COPD-associated exacerbations. (2008). doi: 10.1371/journal.pone.0058945, Luo, X. C., Chen, Z. H., Xue, J. 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. Bronchial epithelial cells from severe asthmatics release paracrine factors such as leukotrienes that can regulate ASM proliferation (Trian et al., 2015) and although antagonists of CysLTR (montelukast) demonstrate significant anti-mitogenic effects in vitro and in vivo; no studies in humans have supported these findings (Halwani et al., 2010; Kelly et al., 2010). doi: 10.1113/expphysiol.2008.042432, Maurer, S., Wabnitz, G. H., Kahle, N. A., Stegmaier, S., Prior, B., Giese, T., et al. doi: 10.1016/j.jaci.2014.02.029, Fakler, B., and Adelman, J. P. (2008). (2012). Unlike ASM cells, expression of TAS2Rs on airway epithelium is restricted to specialized areas suggesting engagement of TAS2Rs in esoteric physiological and pathophysiological functions. Allergy Asthma Rep. 15:72. doi: 10.1007/s11882-015-0571-8, Wu, S., Rozengurt, N., Yang, M., Young, S. H., Sinnett-Smith, J., and Rozengurt, E. (2012). U.S.A. 100, 8981–8986. Biophys. Immunol. J. Chem. Although these approaches provide relief from exacerbations, questions remain on their long-term efficacy and safety. Expression and functional activity of the human bitter taste receptor TAS2R38 in human placental tissues and JEG-3 cells. Immunol. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. (2010). (2015). doi: 10.1152/ajplung.00126.2012, Aoki, M., Takao, T., Takao, K., Koike, F., and Suganuma, N. (2014). Treating mice with bitter taste compounds via inhalation of drug aerosols or intranasal administration results in ablation of most cardinal features of allergen-induced asthma (Sharma et al., 2017). In this review, we will discuss TAS2R biology in distinct cell types associated with the respiratory system, the specific signaling events that ensue TAS2R activation, and the physiological outcomes in cells (in vitro) and integrative model systems (ex vivo and in vivo) relevant to the pathology of obstructive lung diseases. J. Research into TAS2R agonists with increased specificity to receptor subtypes will aid in providing clarity to TAS2R physiology. 123, 322–328.e2. Immunopharmacol. doi: 10.1016/j.cellsig.2006.04.008, Deshpande, D. A., Robinett, K. S., Wang, W. C., Sham, J. S., An, S. S., and Liggett, S. B. Mol. Multiple epithelial cell types possess TAS2R and the key components of the signaling machinery that facilitate intracellular calcium signaling in response to stimulation by bitter agonists (i.e., gustducin, PLCβ2, TRPM5, and IP3R3) (Finger et al., 2003; Tizzano et al., 2006, 2011; Merigo et al., 2007; Gulbransen et al., 2008; Figure 1). Furthermore, the expression of 3 TAS2Rs (13, 14, and 19) has been shown to be significantly increased in asthmatics (Orsmark-Pietras et al., 2013). SCCs also demonstrate unique cooperative capabilities with adjacent cells to enhance innate immunity. FASEB J. Dis. Methods Cell Biol. Furthermore, the distribution of specific TAS2R subtypes within the human bronchial tree is uncharacterized and could possibly account toward variations. Acad. 122, 4145–4159. (2014). In addition to structural cells of the lung tissue, TAS2Rs have also been identified in tissue resident and lung infiltrating immune cells (Orsmark-Pietras et al., 2013; Ekoff et al., 2014). Chem. J. Respir. In this review we discuss the techniques used for elucidating bitter blockers, concept of ligand bias, generic amino acid numbering, the role of cholesterol, and conserved water molecules in the biochemistry and pharmacology of T2Rs. Anti-inflammatory activity of macrolide antibiotics. Nat. In isolated ASM cells from healthy human donors, mRNA transcripts have been confirmed for multiple TAS2R subtypes (Deshpande et al., 2010). Collectively, these findings demonstrate significant capability of TAS2R agonists in regulating ASM cell proliferation. doi: 10.3201/eid0809.020063, Drayna, D. (2005). 56, 762–771. Evidence of solitary chemosensory cells in a large mammal: the diffuse chemosensory system in Bos taurus airways. Furthermore, neither epithelial cell generated nitric oxide nor PGE2 via activation of soluble guanylyl cyclase and prostaglandin receptors respectively, contributes toward TAS2R-mediated airway relaxation. Lung Cell. J. Neurophysiol. (2012). doi: 10.1016/j.lfs.2012.06.014, Lee, R. J., Chen, B., Redding, K. M., Margolskee, R. F., and Cohen, N. A. TAS2R activation promotes airway smooth muscle relaxation despite beta(2)-adrenergic receptor tachyphylaxis. Moreover, these receptors have been evolutionarily engineered to adapt to the tissue environment. Transcripts of different TAS2Rs were confirmed in ASM tissues freshly dissected from human lungs. Using a chronic allergen challenge model, where pathological features of remodeling can be studied extensively, treatment with bitter taste compounds (chloroquine and quinine) reverses cardinal features of airway remodeling (Sharma et al., 2017). Findings from multiple groups suggest that TAS2Rs signaling in ASM cells involves complex interaction of diverse second messengers. In addition to inhibiting cytokine production, our study in isolated human peripheral blood neutrophils suggest that activation of TAS2Rs results in inhibition of migration of immune cells (Sharma et al., 2017). Bitter compounds may also limit airway inflammation by regulating chemotaxis of immune cells and consequently their recruitment to airways (Sharma et al., 2017). In this section we will provide a brief overview of TAS2R expression in individual cell types. Furthermore, in asthmatic ASM cells and lung tissue slices, neither the expression nor the signaling and function of TAS2Rs is impaired under inflammatory conditions (An et al., 2012b; Robinett et al., 2014). Respir Res. For many years, corticosteroids (inhaled and systemic) have been mainstay for management of bronchial inflammation in asthmatics. doi: 10.1073/pnas.1402251111, Saunders, C. J., Reynolds, S. D., and Finger, T. E. (2013). Moreover, each of the TAS2R subtypes can be activated by multiple, chemically diverse group of agonists making the structure-activity relationship very complex. No use, distribution or reproduction is permitted which does not comply with these terms. Science 310, 1495–1499. However, in murine ASM cells and lung slices bitter tastants do not elicit calcium response but inhibit calcium elevation mediated by contractile agonists (Tan and Sanderson, 2014). doi: 10.1183/09031936.00077712. A similar mechanism has been described in neuronal cells where microdomains of concentrated [Ca2+]i are associated with opening of BKCa channels (Fakler and Adelman, 2008). (2010). (2013). We use cookies to help provide and enhance our service and tailor content and ads. (2000). Opin. In cultured ASM cells, our studies reveal elevation in intracellular calcium concentration by a variety of bitter tastants including chloroquine, quinine and saccharine (Deshpande et al., 2010). In ASM cells, activation of TAS2Rs and H1 histamine receptor by ligands (bitter tastants and histamine, respectively) results in generation of [Ca2+]i signals within the cell. Apical localization of K+ channels in taste cells provides the basis for sour taste transduction. (2017). doi: 10.1146/annurev.genom.6.080604.162340, Ekoff, M., Choi, J. H., James, A., Dahlen, B., Nilsson, G., and Dahlen, S. E. (2014). Mol. doi: 10.1016/j.pharmthera.2016.04.002, Plumb, J., Gaffey, K., Kane, B., Malia-Milanes, B., Shah, R., Bentley, A., et al. In asthma, secreted growth factors from infiltrating immune cells and resident epithelial cells can promote ASM cell hyperplasia through PI3 and MAP kinase pathways. Ligand binding at the taste receptors activate second messenger cascades to depolarize the taste cell. 327, 231–247. Biofilms: microbial life on surfaces. Furthermore, in in vivo mouse model studies it was further demonstrated that TAS2R agonists reverse methacholine-induced bronchoconstriction (Deshpande et al., 2010). 6 In lungs, TAS2R expression has been confirmed in multiple airway cell types including airway smooth muscle (ASM) cells, distinct epithelial cell subtypes as well as resident (macrophages) and migratory hematopoietic (neutrophils, mast cells, lymphocytes) inflammatory cells (Shah et al., 2009; Deshpande et al., 2011; Maurer et al., 2015; Tran et al., 2018). Comparing class A GPCRs to bitter taste receptors: structural motifs, ligand interactions and agonist-to-antagonist ratios. As we develop a better understanding of signaling in distinct airway epithelial cell types in normal and diseased state, and other factors that could serve as modulators of TAS2Rs signaling, we may be able to tease out the functional role for specific TAS2R subtypes and tailor specific agonists for desired physiological outcomes (Table 1).


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