ArticleAnesthesiology2015
Antagonists of the TMEM16A calcium-activated chloride channel modulate airway smooth muscle tone and intracellular calcium.
Article in Anesthesiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 55 citations in OpenAlex.
- Triggered Calcium Lightning Programs Cochlear Development.Exploration (Beijing, China) · 2026Article
- Spatiotemporal calcium signaling patterns underlying opposing effects of histamine and TAS2R agonists in airway smooth muscle.American journal of physiology. Lung cellular and molecular physiology · 2025Article
- Unravelling the Role of Post-Junctional M2 Muscarinic Receptors in Cholinergic Nerve-Mediated Contractions of Airway Smooth Muscle.International journal of molecular sciences · 2025Review
- TMEM16A Antagonism: Therapeutic Potential with Desensitization of β-Agonist Responsiveness in Asthma.American journal of respiratory cell and molecular biology · 2025Article
- Inhibition of mucus secretion by niclosamide and benzbromarone in airways and intestine.Scientific reports · 2024Article
- Article
- Pathogenic Relationships in Cystic Fibrosis and Renal Diseases: CFTR, SLC26A9 and Anoctamins.International journal of molecular sciences · 2023Review
- Mechanical stimulation controls osteoclast function through the regulation of CaCommunications biology · 2023Article
- Role of ANO1 in tumors and tumor immunity.Journal of cancer research and clinical oncology · 2022Review
- A determination of pan-pathogen antimicrobials?Medicine in drug discovery · 2022Review
- Anoctamin 1 controls bone resorption by coupling ClNature communications · 2022Article
- Molecular mechanisms of activation and regulation of ANO1-Encoded CaChannels (Austin, Tex.) · 2021Review
- Mucus Release and Airway Constriction by TMEM16A May Worsen Pathology in Inflammatory Lung Disease.International journal of molecular sciences · 2021Article
- The CaActa pharmaceutica Sinica. B · 2021Review
- Calcium-Activated Chloride Channels in Myometrial and Vascular Smooth Muscle.Frontiers in physiology · 2021Review
- The Prognostic Value and Mechanisms of TMEM16A in Human Cancer.Frontiers in molecular biosciences · 2021Review
- 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
- Activation of an Endogenous Opsin 3 Light Receptor Mediates Photo-Relaxation of Pre-Contracting Late Gestation Human Uterine Smooth Muscle Ex Vivo.Reproductive sciences (Thousand Oaks, Calif.) · 2020Article
- Potentiating TMEM16A does not stimulate airway mucus secretion or bronchial and pulmonary arterial smooth muscle contraction.FASEB bioAdvances · 2020Article
- Development of a QPatch-Automated Electrophysiology Assay for Identifying TMEM16A Small-Molecule Inhibitors.Assay and drug development technologies · 2020Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 3 countries.
Funding
Abstract
backgroundPerioperative bronchospasm refractory to β agonists continues to challenge anesthesiologists and intensivists. The TMEM16A calcium-activated chloride channel modulates airway smooth muscle (ASM) contraction. The authors hypothesized that TMEM16A antagonists would relax ASM contraction by modulating membrane potential and calcium flux.
methodsHuman ASM, guinea pig tracheal rings, or mouse peripheral airways were contracted with acetylcholine or leukotriene D4 and then treated with the TMEM16A antagonists: benzbromarone, T16Ainh-A01, N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid, or B25. In separate studies, guinea pig tracheal rings were contracted with acetylcholine and then exposed to increasing concentrations of isoproterenol (0.01 nM to 10 μM) ± benzbromarone. Plasma membrane potential and intracellular calcium concentrations were measured in human ASM cells.
resultsBenzbromarone was the most potent TMEM16A antagonist tested for relaxing an acetylcholine -induced contraction in guinea pig tracheal rings (n = 6). Further studies were carried out to investigate the clinical utility of benzbromarone. In human ASM, benzbromarone relaxed either an acetylcholine- or a leukotriene D4-induced contraction (n = 8). Benzbromarone was also effective in relaxing peripheral airways (n = 9) and potentiating relaxation by β agonists (n = 5 to 10). In cellular mechanistic studies, benzbromarone hyperpolarized human ASM cells (n = 9 to 12) and attenuated intracellular calcium flux from both the plasma membrane and the sarcoplasmic reticulum (n = 6 to 12).
conclusionTMEM16A antagonists work synergistically with β agonists and through a novel pathway of interrupting ion flux at both the plasma membrane and sarcoplasmic reticulum to acutely relax human ASM.
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