Article

TAS2R activation promotes airway smooth muscle relaxation despite β(2)-adrenergic receptor tachyphylaxis.

Program in Respiratory Biology and Lung Disease, Johns Hopkins University, Bloomberg School of Public Health, 615 N Wolfe St., Rm. E-7616, Baltimore, MD 21205, USA.
AJP Lung Cellular and Molecular Physiology (impact factor: 3.66). 06/2012; 303(4):L304-11. DOI:10.1152/ajplung.00126.2012 pp.L304-11
Source: PubMed

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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  • Article: Extraoral bitter taste receptors as mediators of off-target drug effects.
    Adam A Clark, Stephen B Liggett, Steven D Munger
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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; · 5.71 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

ASM undergoes extensive functional desensitization
 
bitter taste receptors
 
cell stiffness
 
chronic obstructive lung disease
 
chronic β-agonists
 
distal common components
 
favorable therapeutic profile
 
human ASM
 
human bronchial responses
 
human lung slices
 
magnetic twisting cytometry
 
mouse tracheal responses
 
phospholipase C activation
 
physiologically relevant cross-desensitization
 
TAS2R desensitization
 
TAS2R function
 
TAS2R relaxation
 
TAS2R-mediated ASM relaxation
 
β(2)-adrenergic receptor
 
β(2)AR desensitization
 

Steven S An