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Expression and function of Anoctamin 1/TMEM16A calcium-activated chloride channels in airways of in vivo mouse models for cystic fibrosis research

  • Molecular and cellular mechanisms of disease
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Abstract

Physiological processes of vital importance are often safeguarded by compensatory systems that substitute for primary processes in case these are damaged by gene mutation. Ca2+-dependent Cl− secretion in airway epithelial cells may provide such a compensatory mechanism for impaired Cl− secretion via cystic fibrosis transmembrane conductance regulator (CFTR) channels in cystic fibrosis (CF). Anoctamin 1 (ANO1) Ca2+-gated Cl− channels are known to contribute to calcium-dependent Cl− secretion in tracheal and bronchial epithelia. In the present study, two mouse models of CF were examined to assess a potential protective function of Ca2+-dependent Cl− secretion, a CFTR deletion model (cftr−/−), and a CF pathology model that overexpresses the epithelial Na+ channel β-subunit (βENaC), which is encoded by the Scnn1b gene, specifically in airway epithelia (Scnn1b-Tg). The expression levels of ANO1 were examined by mRNA and protein content, and the channel protein distribution between ciliated and non-ciliated epithelial cells was analyzed. Moreover, Ussing chamber experiments were conducted to compare Ca2+-dependent Cl− secretion between wild-type animals and the two mouse models. Our results demonstrate that CFTR and ANO1 channels were co-expressed with ENaC in non-ciliated cells of mouse tracheal and bronchial epithelia. Ciliated cells did not express these proteins. Despite co-localization of CFTR and ANO1 in the same cell type, cells in cftr−/− mice displayed no altered expression of ANO1. Similarly, ANO1 expression was unaffected by βENaC overexpression in the Scnn1b-Tg line. These results suggest that the CF-related environment in the two mouse models did not induce ANO1 overexpression as a compensatory system.

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Acknowledgements

We thank Dr. Alexei Diakov for kindly providing the βENaC antibody.

Funding

This project was supported through a grant to AH by the Studienstiftung des deutschen Volkes and in part by the German Ministry for Education and Research (82DZL00401, 82DZL0040A1) to MAM.

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Authors and Affiliations

  1. Department of Animal Molecular Physiology, Centre of Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 504, 69120, Heidelberg, Germany

    Anne Hahn, Dennis Feigenbutz, Lisa Korsch, Ina Lisewski, Katrin Schrimpf, Stephan Frings & Frank Möhrlen

  2. Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Im Neuenheimer Feld 156, 69120, Heidelberg, Germany

    Johanna J. Salomon, Dominik Leitz, Pamela Millar-Büchner & Marcus A. Mall

  3. Department of Pediatric Pulmonology and Immunology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Marcus A. Mall

  4. Berlin Institute of Health (BIH), Berlin, Germany

    Marcus A. Mall

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  1. Anne Hahn
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Correspondence to Stephan Frings.

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Hahn, A., Salomon, J.J., Leitz, D. et al. Expression and function of Anoctamin 1/TMEM16A calcium-activated chloride channels in airways of in vivo mouse models for cystic fibrosis research. Pflugers Arch - Eur J Physiol 470, 1335–1348 (2018). https://doi.org/10.1007/s00424-018-2160-x

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