Inflammatory mediators mediate airway smooth muscle contraction through a G protein-coupled receptor–transmembrane protein 16A–voltage-dependent Ca2+ channel axis and contribute to bronchial hyperresponsiveness in asthma

Wang, Pei; Zhao, Wei; Sun, Jie; Tao, Tao; Chen, Xin; Zheng, Yanyan; Zhang, Cheng–Hai; Zhong, Changqing; Gao, Yun‐Qian; She, Fan; Li, Ye-Qiong; Wei, Lisha; Lü, Ping; Chen, Caiping; Zhou, Ji; Wang, Daquan; Chen, Liang; Shi, Xueping; Deng, Linhong; ZhuGe, Ronghua; Chen, Huaqun; Zhu, Min–Sheng

doi:10.1016/j.jaci.2017.05.053

Cited by 41 publications

(32 citation statements)

References 43 publications

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“…Pharmacological activation of TMEM16A is thought to compensate for the absent CFTR-dependent Cl − secretion in CF, and therefore may represent a CFTR mutation-agnostic therapy [10]. Other studies found a role of TMEM16A for ASM contraction [6,9,11]. Such a role of TMEM16A is particularly evident under inflammatory conditions like asthma, when TMEM16A is strongly upregulated in the ASM.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

Centeio

Cabrita

Benedetto

et al. 2020

IJMS

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TMEM16A is a Ca 2+ activated Cl − channel with important functions in airways, intestine, and other epithelial organs. Activation of TMEM16A is proposed as a therapy in cystic fibrosis (CF) to reinstall airway Cl − secretion and to enhance airway surface liquid (ASL). This CFTR-agnostic approach is thought to improve mucociliary clearance and lung function in CF. This could indeed improve ASL, however, mucus release and airway contraction may also be induced by activators of TMEM16A, particularly in inflamed airways of patients with asthma, COPD, or CF. Currently, both activators and inhibitors of TMEM16A are developed and examined in different types of tissues. Here we compare activation and inhibition of endogenous and overexpressed TMEM16A and analyze potential off-target effects. The three well-known blockers benzbromarone, niclosamide, and Ani9 inhibited both TMEM16A and ATP-induced Ca 2+ increase by variable degrees, depending on the cell type. Niclosamide, while blocking Ca 2+ activated TMEM16A, also induced a subtle but significant Ca 2+ store release and inhibited store-operated Ca 2+ influx. Niclosamide, benzbromarone and Ani9 also affected TMEM16F whole cell currents, indicating limited specificity for these inhibitors. The compounds Eact, cinnamaldehyde, and melittin, as well as the phosphatidylinositol diC8-PIP 2 are the reported activators of TMEM16A. However, the compounds were unable to activate endogenous TMEM16A in HT 29 colonic epithelial cells. In contrast, TMEM16A overexpressed in HEK293 cells was potently stimulated by these activators. We speculate that overexpressed TMEM16A might have a better accessibility to intracellular Ca 2+ , which causes spontaneous activity even at basal intracellular Ca 2+ concentrations. Small molecules may therefore potentiate pre-stimulated TMEM16A currents, but may otherwise fail to activate silent endogenous TMEM16A.

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Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

Centeio

Cabrita

Benedetto

et al. 2020

IJMS

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“…S3). Up-regulated TMEM16A in ASM strongly supports bronchoconstriction (8,26,42). Thus, blockade of TMEM16A will inhibit release of mucus and cytokines and will induce bronchodilation, which should be all beneficial in inflammatory airway disease (8,43).…”

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confidence: 98%

TMEM16A is indispensable for basal mucus secretion in airways and intestine

et al. 2018

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Transmembrane member 16A (TMEM16A) is the Ca2+‐activated chloride channel in airways and intestine. It has been associated with goblet cell metaplasia, as expression of TMEM16A is strongly up‐regulated in cystic fibrosis and asthma during mucus hypersecretion. However, the possible role of TMEM16A for mucus production or mucus secretion remains obscure, and whether TMEM16A controls the function of intestinal goblet cells is entirely unknown. Basal mucus secretion in lungs occurs through low levels of ATP in the airway surface liquid. Here, we report for the first time that TMEM16A is essential for basal secretion of mucus in airways and intestine. Airway‐ciliated and intestinal epithelial‐specific knockout of TMEM16A (TMEM16Aflox/floxFoxJ1, TMEM16Aflox/floxVil1) leads to accumulation of mucus in airway club (Clara) cells and intestinal goblet cells, respectively. Acute ATP‐induced mucus secretion by airway club cells is inhibited when TMEM16A is knocked out in ciliated cells, possibly as a result of compromised release of prosecretory cytokines. Knockdown or inhibition of TMEM16A in human Calu3 airway epithelial cells indicates compromised IL‐8 release. In intestinal goblet cells lacking expression of TMEM16A, mucus accumulates as a result of compromised ATP‐induced secretion. In contrast, cholinergic mucus secretion by compound exocytosis is independent of TMEM16A. The data demonstrate a previously unrecognized role of TMEM16A for membrane exocytosis and describe a novel, ATP‐driven pathway for intestinal mucus secretion. We conclude that ATP‐dependent mucus secretion in both airways and intestine requires TMEM16A. The present results may form the basis for a novel, therapeutic approach for the treatment of mucus hypersecretion in inflammatory airway and intestinal disease.—Benedetto, R., Cabrita, I., Schreiber, R., Kunzelmann, K. TMEM16A is indispensable for basal mucus secretion in airways and intestine. FASEB J. 33, 4502–4512 (2019). http://www.fasebj.org

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“…Activation of this channel causes membrane depolarization with resultant activation of L-type Ca 2ϩ channels (11). Moreover, transgenic mice lacking TMEM16A showed grossly reduced responses to 5-HT and U46619 although their responses to muscarinic stimulation was similar to wild-type mice (46). This suggests that certain inflammatory mediators involved in ASMC contraction require membrane depolarization.…”

Section: Introductionmentioning

confidence: 99%

“…However, there are new developments, which suggest that it is premature to disregard a role for membrane potential-dependent regulation. Recently, it has been shown that the molecular identity of the Ca 2ϩ -activated Cl Ϫ channel in human and mice ASMC is TMEM16A (11,46,49). Activation of this channel causes membrane depolarization with resultant activation of L-type Ca 2ϩ channels (11).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of openers of large-conductance Ca²⁺-activated K⁺ channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle

Bradley

Large

Bihun

et al. 2018

American Journal of Physiology-Cell Physiology

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Airway smooth muscle expresses abundant BKCa channels, but their role in regulating contractions remains controversial. This study examines the effects of two potent BKCa channel openers on agonist-induced phasic contractions in rabbit and mouse bronchi. First, we demonstrated the ability of 10 μM GoSlo-SR5-130 to activate BKCa channels in inside-out patches from rabbit bronchial myocytes, where it shifted the activation V1/2 by −88 ± 11 mV (100 nM Ca2+, n = 7). In mouse airway smooth muscle cells, GoSlo-SR5-130 dose dependently shifted V1/2 by 12–83 mV over a concentration range of 1–30 μM. Compound X, a racemic mixture of two enantiomers, reported to be potent BKCa channel openers, shifted V1/2 by 20–79 mV over a concentration range of 0.3–3 μM. In rabbit bronchial rings, exposure to histamine (1 μM) induced phasic contractions after a delay of ~35 min. These were abolished by GoSlo-SR5-130 (30 μM). Nifedipine (100 nM) and CaCCinhA01 (10 μM), a TMEM16A blocker, also abolished histamine-induced phasic contractions. In mouse bronchi, similar phasic contractions were evoked by exposure to U46619 (100 nM) and carbachol (100 nM). In each case, these were inhibited by concentrations of GoSlo-SR5-130 and compound X that shifted the activation V1/2 of BKCa channels in the order of −80 mV. In conclusion, membrane potential-dependent regulation of L-type Ca2+ channels appears to be important for histamine-, U46619-, and carbachol-induced phasic contractions in airway smooth muscle. Contractions can be abolished by BKCa channel openers, suggesting that these channels are potential targets for treating some causes of airway obstruction.

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Inflammatory mediators mediate airway smooth muscle contraction through a G protein-coupled receptor–transmembrane protein 16A–voltage-dependent Ca2+ channel axis and contribute to bronchial hyperresponsiveness in asthma

Abstract: A G protein-coupled receptor-TMEM16A-voltage-dependent Ca channel axis contributes to inflammatory mediator-induced ASM contraction and synergistically activated TMEM16A by allergic inflammatory mediators with cholinergic stimuli.

Cited by 41 publications

References 43 publications

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

TMEM16A is indispensable for basal mucus secretion in airways and intestine

Inhibitory effects of openers of large-conductance Ca²⁺-activated K⁺ channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle

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Inflammatory mediators mediate airway smooth muscle contraction through a G protein-coupled receptor–transmembrane protein 16A–voltage-dependent Ca2+ channel axis and contribute to bronchial hyperresponsiveness in asthma

Abstract: A G protein-coupled receptor-TMEM16A-voltage-dependent Ca channel axis contributes to inflammatory mediator-induced ASM contraction and synergistically activated TMEM16A by allergic inflammatory mediators with cholinergic stimuli.

Cited by 41 publications

References 43 publications

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

TMEM16A is indispensable for basal mucus secretion in airways and intestine

Inhibitory effects of openers of large-conductance Ca2+-activated K+ channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle

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Product

Resources

About

Inhibitory effects of openers of large-conductance Ca²⁺-activated K⁺ channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle