TAS2R activation promotes airway smooth muscle relaxation despite β(2)-adrenergic receptor tachyphylaxis.
ABSTRACT Recently, bitter taste receptors (TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca(2+) 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 β-agonists. The β(2)-adrenergic receptor (β(2)AR) 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 β(2)AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed >90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of β(2)AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca(2+) concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by >90%. In mouse trachea, β(2)AR desensitization by β-agonist amounted to 92 ± 6.0% (P < 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 ± 3.5%). In human lung slices, chronic β-agonist exposure culminated in 64 ± 5.7% (P < 0.001) desensitization of β(2)AR-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 β-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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ABSTRACT: 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 pre-contracted 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±1.6, 100.0±0.0, 100.0±0.0 and 52.3±1.1 % of maximum, respectively, in the presence of indomethacin) in segments pre-contracted 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 or antigen. The effects of denatonium, but not those of chloroquine were partly inhibited by blockers of the large Ca(2+) activated K(+) channels and decreased by an increase of the level of pre-contraction. In conclusion, TAS2R agonists mediated strong relaxations and substantial inhibition of contractions in guinea-pig trachea. Chloroquine and denatonium had distinct patterns of activity indicating different signalling mechanisms. The findings reinforce the hypothesis that TAS2Rs are potential targets for the development of a new class of more efficacious agonists for bronchodilation.AJP Lung Cellular and Molecular Physiology 09/2012; 303(11). DOI:10.1152/ajplung.00205.2012 · 4.04 Impact Factor
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ABSTRACT: We present a novel hypothesis that could explain many off-target effects of diverse pharmaceuticals. Specifically, we propose that any drug with a bitter taste could have unintended actions in the body through stimulation of extraoral type 2 taste receptors (T2Rs). T2Rs were first identified in the oral cavity, where they function as bitter taste receptors. However, recent findings indicate that they are also expressed outside the gustatory system, including in the gastrointestinal and respiratory systems. T2R ligands include a diverse array of natural and synthetic compounds, many of which are toxins. Notably, many pharmaceuticals taste bitter, with compounds such as chloroquine, haloperidol, erythromycin, procainamide, and ofloxacin known to activate T2Rs. Bitter-tasting compounds can have specific physiological effects in T2R-expressing cells. For example, T2Rs are found in some gastrointestinal endocrine cells, including those that secrete the peptide hormones (e.g., ghrelin and glucagon-like peptide-1) in response to stimulation by bitter-tasting compounds. In the respiratory system, stimulation of T2Rs expressed in respiratory epithelia and smooth muscle has been implicated in protective airway reflexes, ciliary beating, and bronchodilation. If our hypothesis is confirmed, it would offer a new paradigm for understanding the off-target actions of diverse drugs and could reveal potential new therapeutic targets.-Clark, A. A., Liggett, S. B., Munger, S. D. Extraoral bitter taste receptors as mediators of off-target drug effects.The FASEB Journal 09/2012; 26(12). DOI:10.1096/fj.12-215087 · 5.48 Impact Factor
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ABSTRACT: Maintenance of airway tone, prevention of airway obstruction and acute relief from bronchospasm are key targets of asthma therapy. This role is currently performed by β-agonists. However, chronic use of β-agonists to treat asthma is associated with desensitization of β-agonist signaling and a resultant loss of bronchodilator effect, worsening of airway hyperreactivity and increased incidence of asthma-related morbidity and mortality. There have been several attempts to identify novel non-β-agonist bronchodilators including ATP sensitive potassium channel (K(ATP)) agonists such as cromakalim and its active enantiomer BRL-38227, and the cGMP activators atrial natriuretic peptide (ANP) and BAY 41-22722. However these have either not made it to clinical trial, required high doses, had little effect in patients or had a high incidence of side effects. Recent data suggests that a novel bronchodilator target exists, the bitter taste receptor TAS2R. Two recent studies (An SS et al. Am J Physiol Lung Cell Mol Physiol 2012: V. Pulkkinen et al. Am Journal Physiol Lung Cell Mol Physiol 2012.(2, 9)) provide new understanding of the signaling pathways utilized by TAS2Rs to mediate their bronchodilatory effects and how TAS2R mediated bronchodilation is affected by β-agonist signaling desensitization. As our understanding of TAS2Rs and their agonists increases, they move closer to a viable therapeutic option, however further definition is still required and answers remain to be answered. This editorial focus discusses these studies within the context of existing literature and raises questions and challenges for the future development of bitter (better?) therapies for asthma.AJP Lung Cellular and Molecular Physiology 09/2012; 303(11). DOI:10.1152/ajplung.00303.2012 · 4.04 Impact Factor