Agonism of the TMEM16A Calcium-Activated Chloride Channel Modulates Airway Smooth Muscle Tone.

Agonism of the TMEM16A Calcium-Activated Chloride Channel Modulates Airway Smooth Muscle Tone. Am J Physiol Lung Cell Mol Physiol. 2019 Nov 20;: Authors: Danielsson J, Kuforiji AS, Yocum GT, Zhang Y, Xu D, Gallos G, Emala CW Abstract TMEM16A (anoctamin 1) is an important calcium-activated chloride channel (CaCC) in airway smooth muscle (ASM). We have previously shown that TMEM16A antagonists such as benzbromarone relax ASM and have proposed TMEM16A antagonists as novel therapies for asthma treatment. However, TMEM16A is also expressed on airway epithelium, and TMEM16A agonists are being investigated as novel therapies for cystic fibrosis. There are theoretical concerns that agonism of TMEM16A on ASM could lead to bronchospasm making them detrimental as airway therapeutics. The TMEM16A agonist Eact induced a significant contraction of human ASM and guinea pig tracheal rings in an ex vivo organ bath model. Pretreatment with two different TMEM16A antagonists, benzbromarone or T16Ainh-A01, completely attenuated these Eact-induced contractions. Pretreatment with Eact alone augmented the maximum acetylcholine contraction. Pretreatment of A/J mice in vivo with nebulized Eact caused an augmentation of methacholine-induced increases in airway resistance measured by the forced oscillatory technique (Flexivent{trade mark, serif}). Pretreatment with the TMEM16A antagonist benzbromarone significantly attenuated methacholine-induced increases in a...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research