Paradigms and perspectives
Bitter taste receptors in the treatment of asthma: Opportunities and challenges

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Extraoral expression and function of TAS2R

TAS2R are evolutionary conserved proteins in animals that presumably form part of a survival mechanism of chemoperception to sense and avoid potentially harmful food sources. Functional expression studies show these receptors are activated by synthetic as well as natural bitter substances.1 The human genome contains 25 functional, different, relatively small and intronless TAS2R genes expressed on the taste buds of the tongue and palate, as well as 8 pseudogenes. It is thought that the large

TAS2R function in ASM

β2 agonists, muscarinic acetylcholine receptor antagonists, corticosteroids, and xanthines are used to treat various obstructive airway diseases. However, they are not always effective, especially in severe cases, and their prolonged use raises both efficacy and safety concerns due to adverse effects, for example, tachyphylaxis. Although TAS2R are expressed at low levels, significant physiological effects are achieved because GPCRs use a powerful intracellular amplification cascade for

TAS2R as targets for asthma treatment

The ASM-relaxing effect of activated TAS2R is thought to be protective. Other beneficial outcomes of activated bitter taste receptors are their reported anti-inflammatory, antiproliferative, and antifibrotic properties. These effects could have an impact on airway remodeling, hyperplastic growth, and inflammation associated with asthma (Fig 1). Furthermore, an elevation of TAS2R mRNA expression occurs in leukocytes of children with severe asthma versus healthy controls as well as inhibition of

Drug discovery of TAS2R ligands and future investigations

Computationally and molecular modeling approaches developed in the last 5 years can predict the bitterness and toxicity of chemicals, difficult tasks to perform in humans and animals. The database BitterDB lists more than 600 molecules that taste bitter to humans. Among them, almost 10% are medications and about 70% are predicted to be drug-like, a concept that considers oral bioavailability, metabolism, clearance, toxicity, and in vitro pharmacology of candidate medications. Compounds in

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    Transient receptor potential cation channel subfamily M member 5 (TrpM5) is a Ca2+-activated nonselective cation channel that mediates signaling in taste or other chemosensory cells (Zhang et al., 2003; Lu et al., 2017). Activation of Tas2rs by bitter agonists (such as quinine and chloroquine) will trigger a series of downstream signal transduction events, including the release of βγ-subunit from α-gustducin, and subsequent TrpM5 channels opening and taste perception (Deshpande et al., 2010; Camoretti-Mercado and Lockey, 2020). In recent years, this canonical pathway has been increasingly detected outside the oral cavity (Lu et al., 2021).

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    Since chloroquine has been used to treat coronavirus pneumonia (COVID-19) because of its possible antiviral effect (Savarino et al., 2003; Principi and Esposito, 2020), it was suggested that TAS2R10 agonists could, indeed, be used in COVID-19 therapy by acting on viral replication in the upper respiratory tract (Li et al., 2020). Azithromycin was also introduced for the treatment of COVID-19 (Echeverría-Esnal et al., 2021), as it has been found to reduce the production of pro-inflammatory cytokines through the activation of TAS2R10 (Camoretti-Mercado and Lockey, 2020). Moreover, it has been further proven that many flavonoid compounds acting as TAS2R agonists (Meyerhof et al., 2010), such as quercetin, baicalein, and hesperetin, may inhibit key proteins involved in the COVID-19 infective cycle, such as PLpro, 3CLpro, and NTPase/helicase (Meyerhof et al., 2010).

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    Bronchoconstrictive conditions like asthma can be fatal if the airways cannot be dilated. T2R agonists can induce rapid and reversible bronchodilation by reducing reactivity to stimuli like histamine [20–22,23•,24]. Stimulation of T2Rs in ciliated epithelial cells in the bronchi increases ciliary beating, a mechanism to clear irritants from the lungs [25].

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Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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