Future bronchodilator therapy: a bitter pill to swallow?

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 either have 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, Wang WC, Koziol-White CJ, Ahn K, Lee DY, Kurten RC, Panettieri RA Jr, Liggett SB. Am J Physiol Lung Cell Mol Physiol 303: L304-L311, 2012; Pulkkinen V, Manson ML, Säfholm J, Adner M, Dahlén SE. Am J Physiol Lung Cell Mol Physiol. doi:10.1152/ajplung.00205.2012.] 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 questions 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.