The secret life of CFTR as a calcium‐activated chloride channel

Billet, Arnaud; Hanrahan, John W.

doi:10.1113/jphysiol.2013.261909

Cited by 77 publications

(70 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, intracellular Ca 2+ signals not only stimulate basolateral K + channels and supply additional driving force for apical Cl − secretion but also activate CFTR through inhibition of phosphatases and increase of protein kinase C activity (Fig. 7) [4,25,28,42]. Furthermore, a recent report demonstrates that CFTR and Ano1 are separate but functionally related Cl − channels [36].…”

Section: Discussionmentioning

confidence: 92%

Anoctamins support calcium-dependent chloride secretion by facilitating calcium signaling in adult mouse intestine

Schreiber

Faria

Skryabin

et al. 2014

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Intestinal epithelial electrolyte secretion is activated by increase in intracellular cAMP or Ca(2+) and opening of apical Cl(-) channels. In infants and young animals, but not in adults, Ca(2+)-activated chloride channels may cause secretory diarrhea during rotavirus infection. While detailed knowledge exists concerning the contribution of cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) channels, analysis of the role of Ca(2+)-dependent Cl(-) channels became possible through identification of the anoctamin (TMEM16) family of proteins. We demonstrate expression of several anoctamin paralogues in mouse small and large intestines. Using intestinal-specific mouse knockout models for anoctamin 1 (Ano1) and anoctamin 10 (Ano10) and a conventional knockout model for anoctamin 6 (Ano6), we demonstrate the role of anoctamins for Ca(2+)-dependent Cl(-) secretion induced by the muscarinic agonist carbachol (CCH). Ano1 is preferentially expressed in the ileum and large intestine, where it supports Ca(2+)-activated Cl(-) secretion. In contrast, Ano10 is essential for Ca(2+)-dependent Cl(-) secretion in jejunum, where expression of Ano1 was not detected. Although broadly expressed, Ano6 has no role in intestinal cholinergic Cl(-) secretion. Ano1 is located in a basolateral compartment/membrane rather than in the apical membrane, where it supports CCH-induced Ca(2+) increase, while the essential and possibly only apical Cl(-) channel is CFTR. These results define a new role of Ano1 for intestinal Ca(2+)-dependent Cl(-) secretion and demonstrate for the first time a contribution of Ano10 to intestinal transport.

show abstract

Section: Discussionmentioning

confidence: 92%

Anoctamins support calcium-dependent chloride secretion by facilitating calcium signaling in adult mouse intestine

Schreiber

Faria

Skryabin

et al. 2014

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

show abstract

“…CFTR may be swelling activated by release of ATP, which binds to purinergic receptors and increases intracellular Ca 2+ (Almaca et al 2009). CFTR, which is also a Ca 2+ -activated Cl − channel, may therefore be activated by increase in intracellular Ca 2+ (Billet and Hanrahan 2013;Namkung et al 2010;Schreiber et al 2014). Moreover, mechanosensitivity of CFTR has been reported earlier (Vitzthum et al 2015;Zhang et al 2010).…”

Section: Role Of Cftr In Cellular Volume Regulation and Apoptosismentioning

confidence: 95%

Cl− channels in apoptosis

et al. 2016

View full text Add to dashboard Cite

A remarkable feature of apoptosis is the initial massive cell shrinkage, which requires opening of ion channels to allow release of K, Cl, and organic osmolytes to drive osmotic water movement and cell shrinkage. This article focuses on the role of the Cl channels LRRC8, TMEM16/anoctamin, and cystic fibrosis transmembrane conductance regulator (CFTR) in cellular apoptosis. LRRC8A-E has been identified as a volume-regulated anion channel expressed in many cell types. It was shown to be required for regulatory and apoptotic volume decrease (RVD, AVD) in cultured cell lines. Its presence also determines sensitivity towards cytostatic drugs such as cisplatin. Recent data point to a molecular and functional relationship of LRRC8A and anoctamins (ANOs). ANO6, 9, and 10 (TMEM16F, J, and K) augment apoptotic Cl currents and AVD, but it remains unclear whether these anoctamins operate as Cl channels or as regulators of other apoptotic Cl channels, such as LRRC8. CFTR has been known for its proapoptotic effects for some time, and this effect may be based on glutathione release from the cell and increase in cytosolic reactive oxygen species (ROS). Although we find that CFTR is activated by cell swelling, it is possible that CFTR serves RVD/AVD through accumulation of ROS and activation of independent membrane channels such as ANO6. Thus activation of ANO6 will support cell shrinkage and induce additional apoptotic events, such as membrane phospholipid scrambling.

show abstract

“…The simplest explanation of our findings is that the functional linkage is via changes in intracellular Ca 2ϩ . In this regard, it is interesting that Billet and Hanrahan (4) have recently elucidated the pathway whereby Ca 2ϩ -mobilizing cholinergic and purinergic responses activate CFTR (4). Clarification as to whether a similar mechanism may govern epinephrine-stimulated anion secretion in Calu-3 cells and the role of TMEM16A in potentiating this response awaits further experimentation.…”

Section: Discussionmentioning

confidence: 99%