TMEM16A chloride channel does not drive mucus production

Simões, Filipa B.; Quaresma, Margarida C.; Clarke, Luka A.; Silva, Iris; Pankonien, Ines; Railean, Violeta; Kmit, Arthur

doi:10.26508/lsa.201900462

Cited by 28 publications

(37 citation statements)

References 75 publications

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“…The lack of effect of the TMEM16A potentiator ETX001 on goblet cell numbers further challenges the proposed role for TMEM16A channel function as a driver of differentiation towards the mucin producing phenotype. Consistent with our observations, a recent publication has also suggested that the upregulation of MUC5AC and TMEM16A are independent of one another and that there is no role for TMEM16A in goblet cell formation (Simões et al, 2019). One potential explanation for the disconnect between the Simões (2019) report and our present study with the literature may relate to the specificity of the TMEM16A blockers widely used in the earlier studies to establish the phenotype.…”

Section: Discussionsupporting

confidence: 89%

Potentiating TMEM16A channel function has no effect on airway goblet cells or bronchial and pulmonary vascular smooth muscle function

Danahay

Fox

Lilley

et al. 2020

Preprint

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The calcium-activated chloride channel TMEM16A enables chloride secretion across several transporting epithelia, including in the airway where it represents a therapeutic target for the treatment of cystic fibrosis. Additional roles for TMEM16A have also been proposed, including enhancing goblet cell exocytosis, increasing goblet cell numbers and stimulating smooth muscle contraction. The aim of the present study was to test whether the pharmacological regulation of TMEM16A channel function, both potentiation and inhibition, could affect any of these proposed biological roles.In vitro, a recently described potent and selective TMEM16A potentiator (ETX001) failed to stimulate mucin release from primary human bronchial epithelial (HBE) cells over a 24h exposure period using both biochemical and imaging endpoints. In addition, treatment of HBE cells with ETX001 or a potent and selective TMEM16A inhibitor (Ani9) for 4 days did not influence mucin release or goblet cell formation. In vivo, a TMEM16A potentiator was without effect on goblet cell emptying in an IL-13 driven goblet cell metaplasia model.Using freshly isolated human bronchi and pulmonary arteries, neither ETX001 or Ani9 had any effect on the contractile or relaxant responses of the tissues. In vivo, ETX001 also failed to influence either lung or cardiovascular function when delivered directly into the airways of telemetered rats.Together, these studies do not support a role for TMEM16A in the regulation of goblet cell numbers or mucin release, or on the regulation of airway or pulmonary artery smooth muscle contraction.

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Section: Discussionsupporting

confidence: 89%

Potentiating TMEM16A channel function has no effect on airway goblet cells or bronchial and pulmonary vascular smooth muscle function

Danahay

Fox

Lilley

et al. 2020

Preprint

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“…RT-qPCR was performed as previously described [ 19 ]. A list of primers is available in the Supplementary Data .…”

Section: Methodsmentioning

confidence: 99%

KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway

Sousa

Pankonien

Clarke

et al. 2020

Cells

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Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.

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“…CLCA1 is a secreted protein activating currents through endogenous Ca + -activated Cl − channels (CaCCs, such as TMEM16A) (Sala-Rabanal et al, 2015). We found that HRV-A16 increased expression of CLCA1 but not TMEM16A (Simoes et al, 2019) (Supplementary Figure 6). Since previous studies showed that IL-13 does increase expression of CaCCs (Lin et al, 2015;Qin et al, 2016), these findings indicate that pathways leading to increased mucin expression induced by HRV and IL-13 differ.…”

Section: Discussionmentioning

confidence: 91%

Tiotropium and Fluticasone Inhibit Rhinovirus-Induced Mucin Production via Multiple Mechanisms in Differentiated Airway Epithelial Cells

Wang

Ninaber

Schadewijk

et al. 2020

Front. Cell. Infect. Microbiol.

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TMEM16A chloride channel does not drive mucus production

Abstract: Despite being essential for airway hydration, TMEM16A is not required for mucus (MUC5AC) production. Cell proliferation is the main driver for TMEM16A up-regulation during inflammation.

Cited by 28 publications

References 75 publications

Potentiating TMEM16A channel function has no effect on airway goblet cells or bronchial and pulmonary vascular smooth muscle function

Potentiating TMEM16A channel function has no effect on airway goblet cells or bronchial and pulmonary vascular smooth muscle function

KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway

Tiotropium and Fluticasone Inhibit Rhinovirus-Induced Mucin Production via Multiple Mechanisms in Differentiated Airway Epithelial Cells

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