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      TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

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          Abstract

          The inflammatory airway disease cystic fibrosis (CF) is characterized by airway obstruction due to mucus hypersecretion, airway plugging, and bronchoconstriction. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is dysfunctional in CF, leading to defects in epithelial transport. Although CF pathogenesis is still disputed, activation of alternative Cl channels is assumed to improve lung function in CF. Two suitable non-CFTR Cl channels are present in the airway epithelium, the Ca 2+ activated channel TMEM16A and SLC26A9. Activation of these channels is thought to be feasible to improve hydration of the airway mucus and to increase mucociliary clearance. Interestingly, both channels are upregulated during inflammatory lung disease. They are assumed to support fluid secretion, necessary to hydrate excess mucus and to maintain mucus clearance. During inflammation, however, TMEM16A is upregulated particularly in mucus producing cells, with only little expression in ciliated cells. Recently it was shown that knockout of TMEM16A in ciliated cells strongly compromises Cl conductance and attenuated mucus secretion, but does not lead to a CF-like lung disease and airway plugging. Along this line, activation of TMEM16A by denufosol, a stable purinergic ligand, failed to demonstrate any benefit to CF patients in earlier studies. It rather induced adverse effects such as cough. A number of studies suggest that TMEM16A is essential for mucus secretion and possibly also for mucus production. Evidence is now provided for a crucial role of TMEM16A in fusion of mucus-filled granules with the apical plasma membrane and cellular exocytosis. This is probably due to local Ca 2+ signals facilitated by TMEM16A. Taken together, TMEM16A supports fluid secretion by ciliated airway epithelial cells, but also maintains excessive mucus secretion during inflammatory airway disease. Because TMEM16A also supports airway smooth muscle contraction, inhibition rather than activation of TMEM16A might be the appropriate treatment for CF lung disease, asthma and COPD. As a number of FDA-approved and well-tolerated drugs have been shown to inhibit TMEM16A, evaluation in clinical trials appears timely.

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          Most cited references153

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          Airway mucus function and dysfunction.

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            The development of allergic inflammation.

            Allergic disorders, such as anaphylaxis, hay fever, eczema and asthma, now afflict roughly 25% of people in the developed world. In allergic subjects, persistent or repetitive exposure to allergens, which typically are intrinsically innocuous substances common in the environment, results in chronic allergic inflammation. This in turn produces long-term changes in the structure of the affected organs and substantial abnormalities in their function. It is therefore important to understand the characteristics and consequences of acute and chronic allergic inflammation, and in particular to explore how mast cells can contribute to several features of this maladaptive pattern of immunological reactivity.
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              TMEM16A confers receptor-activated calcium-dependent chloride conductance.

              Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                29 January 2019
                2019
                : 10
                : 3
                Affiliations
                [1] 1Institut für Physiologie, Universität Regensburg , Regensburg, Germany
                [2] 2Department of Pediatrics, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague , Prague, Czechia
                [3] 3Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München , Munich, Germany
                [4] 4Innere Medizin I, Klinikum Rechts der Isar der TU München , München, Germany
                Author notes

                Edited by: Nicoletta Pedemonte, Istituto Giannina Gaslini (IRCCS), Italy

                Reviewed by: Carlos A. Flores, Centro de Estudios Científicos, Chile; Jorge Arreola, Universidad Autónoma de San Luis Potosí, Mexico; Alessandra Livraghi-Butrico, University of North Carolina at Chapel Hill, United States

                *Correspondence: Karl Kunzelmann karl.kunzelmann@ 123456ur.de

                This article was submitted to Pharmacology of Ion Channels and Channelopathies, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2019.00003
                6362895
                30761000
                3956bb81-2a3f-47ce-9908-58b08957d31a
                Copyright © 2019 Kunzelmann, Ousingsawat, Cabrita, Doušová, Bähr, Janda, Schreiber and Benedetto.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 August 2018
                : 04 January 2019
                Page count
                Figures: 7, Tables: 3, Equations: 0, References: 181, Pages: 18, Words: 12974
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                tmem16a,anoctamin 1,mucus secretion,cystic fibrosis,asthma,copd,ca2+ signaling

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