TMEM16A Antagonism: Therapeutic Potential with Desensitization of β-Agonist Responsiveness in Asthma

The efficacy of β-agonists in asthma is severely limited by β-adrenoceptor desensitization, which results in poorly managed symptoms and refractory bronchoconstriction. Thus, there is a need to identify novel therapeutic pathways and to clarify the relationship between novel therapeutics and functional β-adrenoceptor responsiveness. We have previously demonstrated that acute antagonism of the calcium-activated chloride channel, transmembrane member 16A (TMEM16A), relaxes airway smooth muscle (ASM). We sought to determine the efficacy and role of TMEM16A antagonism in the context of desensitization β-adrenoceptor responsiveness. For these studies, we exposed murine tracheal rings on wire myography and precision-cut lung slices to contractile mediators in the presence or absence of TMEM16A antagonists and β-agonists with or without prior β-adrenoceptor desensitization. Contractile studies were also performed with human tracheal and bronchial ASM. Finally, the ability of TMEM16A antagonism to prevent desensitization of β₂-adrenoceptor-induced cAMP synthesis was measured in human ASM cells. From these studies, we demonstrate that acute TMEM16A antagonism is effective in relaxing β-agonist-desensitized ASM in central and peripheral murine ASM and human ASM. Furthermore, we demonstrate that chronic pretreatment with TMEM16A antagonists prevents functional desensitization of β-agonist responsiveness in mouse and human upper airways and prevents desensitization of β-agonist-mediated cAMP production in human ASM cells. Taken together, the present study demonstrates a favorable therapeutic profile of TMEM16A antagonism for ASM relaxation despite functional desensitization of β-agonist responsiveness, which may be a novel therapeutic approach in the face of β-adrenoceptor tachyphylaxis.