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CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A
TMEM16A, a Ca(2+)-activated chloride channel (CaCC), and its regulator, CLCA1, are associated with inflammatory airway disease and goblet cell metaplasia. CLCA1 is a secreted protein with protease activity that was demonstrated to enhance membrane expression of TMEM16A. Expression of CLCA1 is partic...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151571/ https://www.ncbi.nlm.nih.gov/pubmed/34066250 http://dx.doi.org/10.3390/ijms22105133 |
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author | Centeio, Raquel Ousingsawat, Jiraporn Schreiber, Rainer Kunzelmann, Karl |
author_facet | Centeio, Raquel Ousingsawat, Jiraporn Schreiber, Rainer Kunzelmann, Karl |
author_sort | Centeio, Raquel |
collection | PubMed |
description | TMEM16A, a Ca(2+)-activated chloride channel (CaCC), and its regulator, CLCA1, are associated with inflammatory airway disease and goblet cell metaplasia. CLCA1 is a secreted protein with protease activity that was demonstrated to enhance membrane expression of TMEM16A. Expression of CLCA1 is particularly enhanced in goblet cell metaplasia and is associated with various lung diseases. However, mice lacking expression of CLCA1 showed the same degree of mucous cell metaplasia and airway hyperreactivity as asthmatic wild-type mice. To gain more insight into the role of CLCA1, we applied secreted N-CLCA1, produced in vitro, to mice in vivo using intratracheal instillation. We observed no obvious upregulation of TMEM16A membrane expression by CLCA1 and no differences in ATP-induced short circuit currents (Iscs). However, intraluminal mucus accumulation was observed by treatment with N-CLCA1 that was not seen in control animals. The effects of N-CLCA1 were augmented in ovalbumin-sensitized mice. Mucus production induced by N-CLCA1 in polarized BCi-NS1 human airway epithelial cells was dependent on TMEM16A expression. IL-13 upregulated expression of CLCA1 and enhanced mucus production, however, without enhancing purinergic activation of Isc. In contrast to polarized airway epithelial cells and mouse airways, which express very low levels of TMEM16A, nonpolarized airway cells express large amounts of TMEM16A protein and show strong CaCC. The present data show an only limited contribution of TMEM16A to airway ion secretion but suggest a significant role of both CLCA1 and TMEM16A for airway mucus secretion. |
format | Online Article Text |
id | pubmed-8151571 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81515712021-05-27 CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A Centeio, Raquel Ousingsawat, Jiraporn Schreiber, Rainer Kunzelmann, Karl Int J Mol Sci Article TMEM16A, a Ca(2+)-activated chloride channel (CaCC), and its regulator, CLCA1, are associated with inflammatory airway disease and goblet cell metaplasia. CLCA1 is a secreted protein with protease activity that was demonstrated to enhance membrane expression of TMEM16A. Expression of CLCA1 is particularly enhanced in goblet cell metaplasia and is associated with various lung diseases. However, mice lacking expression of CLCA1 showed the same degree of mucous cell metaplasia and airway hyperreactivity as asthmatic wild-type mice. To gain more insight into the role of CLCA1, we applied secreted N-CLCA1, produced in vitro, to mice in vivo using intratracheal instillation. We observed no obvious upregulation of TMEM16A membrane expression by CLCA1 and no differences in ATP-induced short circuit currents (Iscs). However, intraluminal mucus accumulation was observed by treatment with N-CLCA1 that was not seen in control animals. The effects of N-CLCA1 were augmented in ovalbumin-sensitized mice. Mucus production induced by N-CLCA1 in polarized BCi-NS1 human airway epithelial cells was dependent on TMEM16A expression. IL-13 upregulated expression of CLCA1 and enhanced mucus production, however, without enhancing purinergic activation of Isc. In contrast to polarized airway epithelial cells and mouse airways, which express very low levels of TMEM16A, nonpolarized airway cells express large amounts of TMEM16A protein and show strong CaCC. The present data show an only limited contribution of TMEM16A to airway ion secretion but suggest a significant role of both CLCA1 and TMEM16A for airway mucus secretion. MDPI 2021-05-12 /pmc/articles/PMC8151571/ /pubmed/34066250 http://dx.doi.org/10.3390/ijms22105133 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Centeio, Raquel Ousingsawat, Jiraporn Schreiber, Rainer Kunzelmann, Karl CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A |
title | CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A |
title_full | CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A |
title_fullStr | CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A |
title_full_unstemmed | CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A |
title_short | CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A |
title_sort | clca1 regulates airway mucus production and ion secretion through tmem16a |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151571/ https://www.ncbi.nlm.nih.gov/pubmed/34066250 http://dx.doi.org/10.3390/ijms22105133 |
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