ArticleAmerican journal of physiology. Lung cellular and molecular physiology2020
Agonism of the TMEM16A calcium-activated chloride channel modulates airway smooth muscle tone.
Article in American journal of physiology. Lung cellular and molecular physiology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 34 citations in OpenAlex.
- Randomized, phase I studies to evaluate the safety, tolerability, and pharmacokinetics of an inhaled, TMEM16A potentiator, GDC-6988, in healthy subjects.Therapeutic advances in respiratory diseaseTrial
- Interplay of CaThe Journal of physiology · 2026Article
- Unravelling the Role of Post-Junctional M2 Muscarinic Receptors in Cholinergic Nerve-Mediated Contractions of Airway Smooth Muscle.International journal of molecular sciences · 2025Review
- Channeling Relaxation through Multiple Means: TMEM16A Antagonism for Asthma.American journal of respiratory cell and molecular biology · 2025Article
- TMEM16A Antagonism: Therapeutic Potential with Desensitization of β-Agonist Responsiveness in Asthma.American journal of respiratory cell and molecular biology · 2025Article
- A 5-HT-mediated urethral defense against urinary tract infections.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Tamsulosin ameliorates bone loss by inhibiting the release of ClProceedings of the National Academy of Sciences of the United States of America · 2025Article
- ANO1: central role and clinical significance in non-neoplastic and neoplastic diseases.Frontiers in immunology · 2025Review
- Inhibition of mucus secretion by niclosamide and benzbromarone in airways and intestine.Scientific reports · 2024Article
- Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle.International journal of molecular sciences · 2023Review
- Discovery of Fungus-Derived Nornidulin as a Novel TMEM16A Inhibitor: A Potential Therapy to Inhibit Mucus Secretion in Asthma.Journal of experimental pharmacology · 2023Article
- Anoctamin 1 controls bone resorption by coupling ClNature communications · 2022Article
- Molecular mechanisms of activation and regulation of ANO1-Encoded CaChannels (Austin, Tex.) · 2021Review
- The diverse roles of TMEM16A CaJournal of advanced research · 2021Review
- Mucus Release and Airway Constriction by TMEM16A May Worsen Pathology in Inflammatory Lung Disease.International journal of molecular sciences · 2021Article
- Reciprocal Correlations of Inflammatory and Calcium Signaling in Asthma Pathogenesis.Advances in experimental medicine and biology · 2021Article
- The odorant receptor OR2W3 on airway smooth muscle evokes bronchodilation via a cooperative chemosensory tradeoff between TMEM16A and CFTR.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Potentiating TMEM16A does not stimulate airway mucus secretion or bronchial and pulmonary arterial smooth muscle contraction.FASEB bioAdvances · 2020Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
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.
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