Epithelial Chloride Transport by CFTR Requires TMEM16A

Benedetto, Roberta Di; Ousingsawat, Jiraporn; Wanitchakool, Podchanart; Zhang, Yong; Holtzman, Michael J.; Amaral, Margarida D.; Rock, Jason R.; Schreiber, Rainer; Kunzelmann, Karl

doi:10.1038/s41598-017-10910-0

Cited by 108 publications

(173 citation statements)

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“…However, we know that NFA inhibits other TMEM16 paralogues as well and blocks K + and Ca 2+ channels (12,13). Rather surprisingly, knockout of the dominating Cl 2 channel TMEM16A in ciliated epithelial cells does not lead to a CF-like lung phenotype in adult mice (14). Here, we report a defect of secretion and an accumulation of mucus in secretory cells when TMEM16A is knocked out in ciliated airway epithelial cells or intestinal goblet cells.…”

mentioning

confidence: 64%

“…Airways lacking epithelial cell-specific expression of TMEM16A (14) demonstrated an impressive accumulation of mucus, which was not a result of an increased fraction of nonciliated club (Clara) cells ( Fig. 1A-C and Supplemental Fig.…”

Section: Inhibition Of Basal Airway Mucus Secretion In the Absence Ofmentioning

confidence: 97%

“…Generation of mice with intestinal epithelial knockout of TMEM16A [TMEM16A flox/flox Vil1-Cre (fl/fl-Vil1)] has been described earlier (17). Tissue-specific knockout of TMEM16A in ciliated airway epithelial cells was achieved by the crossbreeding of TMEM16A flox/flox (fl/fl) mice with TMEM16A flox/flox FoxJ1-Cre (fl/ fl-FoxJ1) mice and is outlined in Benedetto et al (14). Allergen challenge of mice has been described in Schreiber et al (18).…”

Section: Tmem16a Knockout Animals Ovalbumin Challenge and Preparatimentioning

confidence: 99%

“…Extracellular Cl 2 (145 mM) was replaced by gluconate, HCO 3 2 , or I 2 . Experiments were performed as described in Benedetto et al (14).…”

Section: Patch Clampingmentioning

confidence: 99%

“…Tracheas were removed, fixed with insect needles onto extrathick blot paper (Bio-Rad, Munich, Germany), and transferred into a chamber with a water-saturated atmosphere at 37°C. Transport was measured as described in Benedetto et al (14).…”

Section: Mucociliary Transport Ex Vivomentioning

confidence: 99%

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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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mentioning

confidence: 64%

Section: Inhibition Of Basal Airway Mucus Secretion In the Absence Ofmentioning

confidence: 97%

Section: Tmem16a Knockout Animals Ovalbumin Challenge and Preparatimentioning

confidence: 99%

“…Extracellular Cl 2 (145 mM) was replaced by gluconate, HCO 3 2 , or I 2 . Experiments were performed as described in Benedetto et al (14).…”

Section: Patch Clampingmentioning

confidence: 99%

Section: Mucociliary Transport Ex Vivomentioning

confidence: 99%

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TMEM16A is indispensable for basal mucus secretion in airways and intestine

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Physiology of Electrolyte Transport in the Gut: Implications for Disease

Rao

2019

Comprehensive Physiology

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We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR‐CAS technology, stem cell‐derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na + /K + ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl − channels and the basolateral Na + ‐K + ‐2Cl − cotransporter, NKCC1 and K + channels. Absorption chiefly involves apical membrane Na + /H + exchangers and Cl − /HCO 3 − exchangers in the small intestine and proximal colon and Na + channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947‐1023, 2019.

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