Abstract
Author SummaryBitter taste receptors (TAS2Rs), a G-protein-coupled receptor family long thought to be solely expressed in taste buds on the tongue, have recently been detected in airways. Bitter substances can activate TAS2Rs in airway smooth muscle to cause greater bronchodilation than β2 adrenergic receptor agonists, the most commonly used bronchodilators. However, the mechanisms underlying this bronchodilation remain elusive. Here we show that, in resting primary airway smooth muscle cells, bitter tastants activate a TAS2R-dependent signaling pathway that results in an increase in intracellular calcium levels, albeit to a level much lower than that produced by bronchoconstrictors. In bronchoconstricted cells, however, bitter tastants reverse the bronchoconstrictor-induced increase in calcium levels, which leads to the relaxation of smooth muscle cells. We find that this reversal is due to inhibition of L-type calcium channels. Our results suggest that under normal conditions, bitter tastants can activate TAS2Rs to modestly increase calcium levels, but that when smooth muscle cells are constricted, they can block L-type calcium channels to induce bronchodilation. We postulate that this novel mechanism could operate in other extraoral cells expressing TAS2Rs.
Highlights
Airway obstructive diseases have become increasingly prevalent, currently affecting more than 300 million people worldwide
In resting primary airway smooth muscle cells, bitter tastants activate a TAS2R-dependent signaling pathway that results in an increase in intracellular calcium levels, albeit to a level much lower than that produced by bronchoconstrictors
Our results suggest that under normal conditions, bitter tastants can activate TAS2Rs to modestly increase calcium levels, but that when smooth muscle cells are constricted, they can block L-type calcium channels to induce bronchodilation
Summary
Airway obstructive diseases (asthma and chronic obstructive pulmonary disease [COPD]) have become increasingly prevalent, currently affecting more than 300 million people worldwide. Dysfunction of airway smooth muscle (ASM) cells, a major cell type in the respiratory tree, plays a pivotal role in promoting progression of these diseases and in contributing to their symptoms of these diseases [1,2,3]. With their ability to contract and relax, these cells regulate the diameter and length of conducting airways, controlling dead space and resistance to airflow to and from gasexchanging areas. A better understanding of the mechanisms regulating ASM holds the promise of developing more effective and safe bronchodilators, which in turn would have a significant impact in reducing mortality and morbidity caused by asthma and COPD
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