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

Abstract

(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.

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

“…Although we could not find a specific G protein-coupled pathway in this first description of relaxation of guinea pig airways induced by activation of bitter taste receptors, the potency of the bitter taste agonists showed clear similarities to human expression systems (16). Taken together with previous findings in other species and models (3,5,7,19), our findings reinforce that TAS2Rs are potential new targets for development of a novel class of bronchodilators. Priority should now be given to define the signaling mechanisms and to identify agonists, which are more potent and selective.…”

“…The finding that neither ␤ 2 -adrenoceptor agonists produced maximum relaxation at the highest preload indicates that the bitter taste agonists have a greater efficacy than the ␤ 2 -adrenoceptor agonists and induce smooth muscle relaxation by other mechanisms. These distinct mechanisms between bitter taste agonists and ␤ 2 -adrenoceptor agonists were recently shown also by the lack of interference in desensitization experiments (3).…”

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

“…Aerosol exposure of airways to TAS2R agonists results in bronchodilation in normal and allergen-sensitized and -challenged mice. In a recent study by Robinett et al using asthmatic ASM cells and lung slices, TAS2R expression, signaling, and ASM relaxation and bronchodilatory effects were not altered under airway inflammatory conditions (1,46). These studies suggest that agonists of TAS2Rs possess unique properties that can be exploited as a new class of antiasthma drugs (16,34).…”

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…There has been considerable excitement regarding the identification of bitter taste receptors (BTRs) as novel bronchodilators (4,43,61,82,241,262,352). Of the 25 members in this family of GPCRs (type 2, bitter taste receptors, TAS2Rs; Fig.…”