Agonism of the TMEM16A calcium-activated chloride channel modulates airway smooth muscle tone.

Author(s) Danielsson, J.; Kuforiji, A.S.; Yocum, G.T.; Zhang, Y.; Xu, D.; Gallos, G.; Emala, C.W.
Journal Am J Physiol Lung Cell Mol Physiol
Date Published 2020 Feb 01
Abstract

TMEM16A (anoctamin 1) is an important calcium-activated chloride channel 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). Pretreatment with the TMEM16A antagonist benzbromarone significantly attenuated methacholine-induced increases in airway resistance. In in vitro cellular studies, TMEM16A was found to be expressed more abundantly in ASM compared with epithelial cells in culture (8-fold higher in ASM). Eact caused an increase in intracellular calcium in human ASM cells that was completely attenuated by pretreatment with benzbromarone. Eact acutely depolarized the plasma membrane potential of ASM cells, which was attenuated by benzbromarone or nifedipine. The TMEM16A agonist Eact modulates ASM contraction in both ex vivo and in vivo models, suggesting that agonism of TMEM16A may lead to clinically relevant bronchospasm.

DOI 10.1152/ajplung.00552.2018
ISSN 1522-1504
Citation Danielsson J, Kuforiji AS, Yocum GT, Zhang Y, Xu D, Gallos G, et al. Agonism of the TMEM16A calcium-activated chloride channel modulates airway smooth muscle tone. Am J Physiol Lung Cell Mol Physiol. 2020;318(2):L287-L295.

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