TMEM16A Mediates Mucus Production in Human Airway Epithelial Cells

Cabrita, Inês; Benedetto, Roberta Di; Wanitchakool, Podchanart; Lérias, Joana R.; Centeio, Raquel; Ousingsawat, Jiraporn; Schreiber, Rainer; Kunzelmann, Karl

doi:10.1165/rcmb.2019-0442oc

Cited by 29 publications

(37 citation statements)

References 41 publications

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“…The present and previous data [ 16 ] data suggest an important role of TMEM16A for IL-13 and CLCA1-induced mucus/MUC5AC production. We explored the role of TMEM16A/CLCA1 also in polarized grown BCi-NS1 human airway epithelial cells [ 16 , 31 ]. While expression of both TMEM16A and CLCA1 was very low in these cells, exposure of the cells to IL-13 increased expression of both proteins ( Figure 6 A).…”

Section: Resultssupporting

confidence: 79%

“…However, CLCA1 may have also contributed to unfolding and expansion of airway mucus, similar to unfolding of intestinal mucus [ 25 , 52 ]. Although CLCA1 was proposed to induce this effect by activating CaCC/TMEM16A in vitro [ 16 , 17 , 18 , 19 , 20 , 21 , 53 ], our present in vivo data do not indicate an upregulation of TMEM16A currents in mouse trachea. Thus, our data agree with other in vivo studies that indicate (i) no contribution of CLCA1 chloride conductance in mouse airways [ 24 ] and (ii) no inhibition of CLCA1-indued mucus expansion by TMEM16A channel blockers in mouse intestine [ 25 ].…”

Section: Discussioncontrasting

confidence: 82%

“…These effects of N-CLCA1 may be related to the mucus expanding properties of CLCA1 described earlier [ 25 ]. However, as previous studies demonstrated a role of TMEM16A for mucus secretion, N-CLCA1 may also induce mucus secretion through an increase in TMEM16A-function [ 5 , 16 , 21 ].…”

Section: Resultsmentioning

confidence: 99%

“…Above data indicate an upregulation of TMEM16A expression under asthmatic conditions and by the cytokine IL-13 [ 16 ]. N-CLCA1, in contrast, did not induce expression of TMEM16A in Calu3 cells ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

“…Many studies associate expression of TMEM16A and the regulator of Ca 2+ -activated Cl − channels, CLCA1, with goblet cell metaplasia and mucus production/secretion [ 3 , 4 , 5 , 14 , 15 , 16 , 17 ]. Inflammatory airway disease is associated with enhanced expression of CLCA1 in airway epithelial cells and high levels in the bronchoalveolar lavage (BAL) fluid [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A

Centeio

Ousingsawat

Schreiber

et al. 2021

IJMS

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TMEM16A, a Ca2+-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.

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Section: Resultssupporting

confidence: 79%

Section: Discussioncontrasting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A

Centeio

Ousingsawat

Schreiber

et al. 2021

IJMS

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Characteristics of mucin hypersecretion in different inflammatory patterns based on endotypes of chronic rhinosinusitis

Zhai,

Shao,

et al. 2024

Clinical & Translational All

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BackgroundChronic rhinosinusitis (CRS) is usually accompanied by mucin hypersecretion that can lead to mucus accumulation and impair nasal mucociliary clearance, thus exacerbating airway inflammation. Abnormal mucin hypersecretion is regulated by different T helper (Th) cytokines, which are associated with different endotype‐driven inflammatory responses. Therefore, it is of great significance to understand how these factors regulate mucin hypersecretion to provide precise treatment strategies for different endotypes of CRS.BodyThus far, the most common endotypes of CRS are classified as type 1, type 2, or type 3 immune responses based on innate and adaptive cell‐mediated effector immunity, and the representative Th cytokines in these immune responses, such as IFN‐γ, TNF‐α, IL‐4, IL‐5, IL‐13, IL‐10, IL‐17, and IL‐22, play an important regulatory role in mucin secretion. We reviewed all the related literature in the PubMed database to determine the expression of these Th cytokines in CRS and the role they play in the regulation of mucin secretion.ConclusionWe believe that the main Th cytokines involved in specific endotypes of CRS play a key role in regulating abnormal mucin secretion, which contributes to better understanding of the pathogenesis of CRS and provides therapeutic targets for airway inflammatory diseases associated with mucin hypersecretion.

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KCNE1 does not shift TMEM16A from a Ca2+ dependent to a voltage dependent Cl- channel and is not expressed in renal proximal tubule

Talbi

Ousingsawat

Centeio

et al. 2023

Pflugers Arch - Eur J Physiol

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The TMEM16A (ANO1) Cl- channel is activated by Ca2+ in a voltage-dependent manner. It is broadly expressed and was shown to be also present in renal proximal tubule (RPT). KCNQ1 is an entirely different K+ selective channel that forms the cardiac IKS potassium channel together with its ß-subunit KCNE1. Surprisingly, KCNE1 has been claimed to interact with TMEM16A, and to be required for activation of TMEM16A in mouse RPT. Interaction with KCNE1 was reported to switch TMEM16A from a Ca22+-dependent to a voltage-dependent ion channel. Here we demonstrate that KCNE1 is not expressed in mouse RPT. TMEM16A expressed in RPT is activated by angiotensin II and ATP in a KCNE1-independent manner. Coexpression of KCNE1 does not change TMEM16A to a voltage gated Cl- channel and Ca2+-dependent regulation of TMEM16A is fully maintained in the presence of KCNE1. While overexpressed KCNE1 slightly affects Ca2+-dependent regulation of TMEM16A, the data provide no evidence for KCNE1 being an auxiliary functional subunit for TMEM16A.

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TMEM16A Mediates Mucus Production in Human Airway Epithelial Cells

Cited by 29 publications

References 41 publications

CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A

CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A

Characteristics of mucin hypersecretion in different inflammatory patterns based on endotypes of chronic rhinosinusitis

KCNE1 does not shift TMEM16A from a Ca2+ dependent to a voltage dependent Cl- channel and is not expressed in renal proximal tubule

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