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      TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis

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          Abstract

          Rationale: Enhancing non–CFTR (cystic fibrosis transmembrane conductance regulator)-mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis (CF) and other mucoobstructive diseases.

          Objectives: To determine the effects of TMEM16A potentiation on epithelial fluid secretion and mucociliary clearance.

          Methods: The effects of a novel low-molecular-weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport.

          Measurements and Main Results: Potentiating the activity of TMEM16A with ETX001 increased the Ca 2+-activated Cl channel activity and anion secretion in human bronchial epithelial (HBE) cells from patients with CF without impacting calcium signaling. ETX001 rapidly increased fluid secretion and airway surface liquid height in CF-HBE cells under both static conditions and conditions designed to mimic the shear stress associated with tidal breathing. In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional.

          Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with CF and non-CF mucoobstructive diseases.

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          Most cited references38

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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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            TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity.

            Calcium-dependent chloride channels are required for normal electrolyte and fluid secretion, olfactory perception, and neuronal and smooth muscle excitability. The molecular identity of these membrane proteins is still unclear. Treatment of bronchial epithelial cells with interleukin-4 (IL-4) causes increased calcium-dependent chloride channel activity, presumably by regulating expression of the corresponding genes. We performed a global gene expression analysis to identify membrane proteins that are regulated by IL-4. Transfection of epithelial cells with specific small interfering RNA against each of these proteins shows that TMEM16A, a member of a family of putative plasma membrane proteins with unknown function, is associated with calcium-dependent chloride current, as measured with halide-sensitive fluorescent proteins, short-circuit current, and patch-clamp techniques. Our results indicate that TMEM16A is an intrinsic constituent of the calcium-dependent chloride channel. Identification of a previously unknown family of membrane proteins associated with chloride channel function will improve our understanding of chloride transport physiopathology and allow for the development of pharmacological tools useful for basic research and drug development.
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              Expression cloning of TMEM16A as a calcium-activated chloride channel subunit.

              Calcium-activated chloride channels (CaCCs) are major regulators of sensory transduction, epithelial secretion, and smooth muscle contraction. Other crucial roles of CaCCs include action potential generation in Characean algae and prevention of polyspermia in frog egg membrane. None of the known molecular candidates share properties characteristic of most CaCCs in native cells. Using Axolotl oocytes as an expression system, we have identified TMEM16A as the Xenopus oocyte CaCC. The TMEM16 family of "transmembrane proteins with unknown function" is conserved among eukaryotes, with family members linked to tracheomalacia (mouse TMEM16A), gnathodiaphyseal dysplasia (human TMEM16E), aberrant X segregation (a Drosophila TMEM16 family member), and increased sodium tolerance (yeast TMEM16). Moreover, mouse TMEM16A and TMEM16B yield CaCCs in Axolotl oocytes and mammalian HEK293 cells and recapitulate the broad CaCC expression. The identification of this new family of ion channels may help the development of CaCC modulators for treating diseases including hypertension and cystic fibrosis.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                15 April 2020
                15 April 2020
                15 April 2020
                15 April 2020
                : 201
                : 8
                : 946-954
                Affiliations
                [ 1 ]Enterprise Therapeutics, Brighton, United Kingdom
                [ 2 ]Sussex Drug Discovery Centre, University of Sussex, Brighton, United Kingdom
                [ 3 ]Mount Sinai Medical Center of Florida, Miami, Florida; and
                [ 4 ]Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
                Author notes
                Correspondence and requests for reprints should be addressed to Martin Gosling, Ph.D., Enterprise Therapeutics, Sussex Innovation Centre, Falmer, Brighton BN1 9SB, UK. E-mail: martin@ 123456enterprisetherapeutics.com .
                Article
                201908-1641OC
                10.1164/rccm.201908-1641OC
                7159426
                31898911
                90f29ba7-5df4-4d76-87fa-1ef85bf170d7
                Copyright © 2020 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

                History
                : 21 August 2019
                : 20 December 2019
                Page count
                Figures: 5, Tables: 0, Pages: 9
                Categories
                Original Articles
                Cystic Fibrosis

                mucus clearance,mucus hydration,anoctamin-1,calcium-activated chloride channel

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