Reply to: Activation of BK channels may not be required for bitter tastant–induced bronchodilation

An, Steven S.; Robinett, Kathryn S.; Deshpande, Deepak A.; Wang, Wayne C. H.; Liggett, Stephen B.

doi:10.1038/nm.2734

Cited by 21 publications

(23 citation statements)

References 13 publications

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“…3B). On the other hand, chloroquine induced complete relaxation of GPT precontracted with the EP 1 /EP 3 receptor agonist 17-phenyl trinor PGE 2 (Fig. 3B).…”

Section: Resultsmentioning

confidence: 93%

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The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea

Pulkkinen

Manson

Säfholm

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulkkinen V, Manson ML, Säfholm J, Adner M, Dahlén S. The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea. Am J Physiol Lung Cell Mol Physiol 303: L956 -L966, 2012. First published September 7, 2012 doi:10.1152/ajplung.00205.2012.-Activation of taste receptors (TAS2Rs) by bitter taste agonists has been reported to cause bronchodilation. The aim of this study was to extend the information on the effects of bitter taste agonists on responses induced by different contractile mediators in a standard airway physiology preparation. Isometric responses were assessed in guinea pig trachea (GPT). TAS2R agonists were administered either to segments precontracted with different agonists for contraction or given before challenge with the different contractile stimuli, including antigen in tissues from ovalbumin-sensitized animals. TAS2R mRNA expression on GPT epithelium and smooth muscle was measured with real-time PCR. Denatonium, chloroquine, thiamine, and noscapine induced concentration-dependent relaxations (R max: 98.3 Ϯ 1.6, 100.0 Ϯ 0.0, 100.0 Ϯ 0.0, and 52.3 Ϯ 1.1% of maximum, respectively, in the presence of indomethacin) in segments precontracted with carbachol. The receptors for denatonium (TAS2R4, TAS2R10) and chloroquine (TAS2R3, TAS2R10) were expressed in GPT. Whereas denatonium selectively inhibited contractions induced by carbachol, chloroquine uniformly inhibited contractions evoked by prostaglandin E 2, the thromboxane receptor agonist U-46619, leukotriene D 4, histamine, and antigen. The effects of denatonium, but not those of chloroquine, were partly inhibited by blockers of the large Ca 2ϩ -activated K ϩ channels and decreased by an increase of the level of precontraction. In conclusion, TAS2R agonists mediated strong relaxations and substantial inhibition of contractions in GPT. Chloroquine and denatonium had distinct patterns of activity, indicating different signaling mechanisms. The findings reinforce the hypothesis that TAS2Rs are potential targets for the development of a new class of more efficacious agonists for bronchodilation. bronchodilation; asthma; prostaglandins; airway smooth muscle BITTER TASTE-SENSING TYPE 2 receptors (TAS2Rs) are G proteincoupled receptors (GPCRs) on cell surface that mediate gustatory taste perception on the tongue (16). The properties of TAS2Rs are different from many other GPCRs, as the receptors are promiscuous and capable of binding a wide range of compounds with relatively low specificity and affinity (16). TAS2Rs have recently been suggested to have important extraoral functions in the respiratory and gastrointestinal tracts (4, 11). In the human airway epithelium, TAS2Rs are expressed on the solitary chemosensory cells (25,26) and ciliated epithelial cells (23), where they sense chemical irritation and promote ciliary beat frequency, respectively. Thus TAS2Rs may be protective and part of the defense against inhaled noxious compounds.Recently airway smooth muscle cells were foun...

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“…3B). On the other hand, chloroquine induced complete relaxation of GPT precontracted with the EP 1 /EP 3 receptor agonist 17-phenyl trinor PGE 2 (Fig. 3B).…”

Section: Resultsmentioning

confidence: 93%

“…However, An et al (2) found the chloroquine-induced relaxation of mouse trachea and human airway smooth muscle to be partially sensitive to BK Ca channel blockers. It is likely that methodological issues and species differences in bitter taste receptor homolog expression could contribute to different results in different systems.…”

Section: L964mentioning

confidence: 99%

The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea

Pulkkinen

Manson

Säfholm

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Paradoxically, the stimulation of bitter taste receptors in human airway smooth muscle cells induced relaxation following a localized increase in intracellular calcium, which in turn caused membrane hyperpolarization via the activation of large conductance potassium channels (BK Ca ) [1]. This observation was then partly confirmed in studies of mouse [13,14] and guinea pig airways [10] while another most recent hypothesis to explain the relaxant effect of chloroquine in mouse airways was the inhibition of L-type voltage-gated calcium channels [15]. Altogether, these data demonstrate that the exact mechanism of bitter taste-induced airway relaxation remains poorly known - particularly in human whole tissues.…”

Section: Introductionmentioning

confidence: 99%

The expression and relaxant effect of bitter taste receptors in human bronchi

et al. 2013

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BackgroundBitter-taste receptors (TAS2Rs) have recently been involved in the relaxation of mouse and guinea pig airways, and increased expression of TAS2Rs was shown in blood leucocytes from asthmatic children. We sought to identify and characterize the TAS2Rs expressed in isolated human bronchi and the subtypes involved in relaxation.MethodsHuman bronchi were isolated from resected lungs and TAS2R transcripts were assessed with RT-qPCR. Relaxation to TAS2R agonists was tested in organ bath in the presence or absence of pharmacological modulators of the signalling pathways involved in bronchial relaxation.ResultsWe detected the expression of TAS2R transcripts in human bronchi. The non-selective agonists chloroquine, quinine, caffeine, strychnine and diphenidol produced a bronchial relaxation as effective and potent as theophylline but much less potent than formoterol and isoproterenol. Denatonium, saccharin and colchicine did not produce relaxation. Receptor expression analysis together with the use of selective agonists suggest a predominant role for TAS2R5, 10 and 14 in bitter taste agonist-induced relaxation. The mechanism of relaxation was independent of the signalling pathways modulated by conventional bronchodilators and may be partly explained by the inhibition of phosphatidylinositol-3-kinases.ConclusionsThe TAS2Rs may constitute a new therapeutic target in chronic obstructive lung diseases such as asthma.

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“…One such class of receptors is the bitter taste receptors (TAS2Rs), some of which are expressed at levels greater than ␤ 2 AR (18 (18) and potentially other mechanisms (5). In isolated human bronchi, TAS2R agonist-mediated relaxation appears to be equal to or somewhat greater than that of the full ␤-agonist isoproterenol (17,18).…”

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confidence: 99%

TAS2R activation promotes airway smooth muscle relaxation despite β₂-adrenergic receptor tachyphylaxis

Wang

Koziol‐White

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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(TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca 2ϩ concentration signaling generated from restricted phospholipase C activation. As potential therapy, TAS2R agonists could be add-on treatment when patients fail to achieve adequate bronchodilation with chronic ␤-agonists. The ␤2-adrenergic receptor (␤2AR) of ASM undergoes extensive functional desensitization. It remains unknown whether this desensitization affects TAS2R function, by cross talk at the receptors or distal common components in the relaxation machinery. We studied intracellular signaling and cell mechanics using isolated human ASM, mouse tracheal responses, and human bronchial responses to characterize TAS2R relaxation in the context of ␤ 2AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed Ͼ90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of ␤ 2AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca 2ϩ concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by Ͼ90%. In mouse trachea, ␤ 2AR desensitization by ␤-agonist amounted to 92 Ϯ 6.0% (P Ͻ 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 Ϯ 3.5%). In human lung slices, chronic ␤-agonist exposure culminated in 64 Ϯ 5.7% (P Ͻ 0.001) desensitization of ␤ 2AR-mediated dilation of carbachol-constricted airways that was reversed by chloroquine. We conclude that there is no evidence for physiologically relevant cross-desensitization of TAS2R-mediated ASM relaxation from chronic ␤-agonist treatment. These findings portend a favorable therapeutic profile for TAS2R agonists for the treatment of bronchospasm in asthma or chronic obstructive lung disease.

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Reply to: Activation of BK channels may not be required for bitter tastant–induced bronchodilation

Cited by 21 publications

References 13 publications

The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea

The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea

The expression and relaxant effect of bitter taste receptors in human bronchi

TAS2R activation promotes airway smooth muscle relaxation despite β₂-adrenergic receptor tachyphylaxis

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Reply to: Activation of BK channels may not be required for bitter tastant–induced bronchodilation

Cited by 21 publications

References 13 publications

The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea

The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea

The expression and relaxant effect of bitter taste receptors in human bronchi

TAS2R activation promotes airway smooth muscle relaxation despite β2-adrenergic receptor tachyphylaxis

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Product

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TAS2R activation promotes airway smooth muscle relaxation despite β₂-adrenergic receptor tachyphylaxis