TMEM16F (Anoctamin 6), an anion channel of delayed Ca2+ activation

Grubb, Søren; Poulsen, Kristian Arild; Juul, Christian Ammitzbøll; Kyed, Tania; Klausen, Thomas Kjær; Larsen, Erik Hviid; Hoffmann, Else K.

doi:10.1085/jgp.201210861

Cited by 109 publications

(167 citation statements)

References 61 publications

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“…For ANO6/ TMEM16F, a similar role has been described recently (Juul et al 2014;Ousingsawat et al 2015;Sirianant et al 2015). ANO6 is a Ca 2+ -activated phospholipid scramblase that may also operate as a Ca 2+ -activated Cl − or nonselective ion channel (Grubb et al 2013;Kunzelmann et al 2014;Shimizu et al 2013;Suzuki et al 2010;Tian et al 2012;Yang et al 2012). We found that ANO6 is activated by hypotonic cell swelling, or, alternatively, controls the activity of VRAC .…”

Section: Role Of Tmem16f/ano6 In Volume Regulation and Regulated Cellsupporting

confidence: 77%

Cl− channels in apoptosis

et al. 2016

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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.

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Section: Role Of Tmem16f/ano6 In Volume Regulation and Regulated Cellsupporting

confidence: 77%

Cl− channels in apoptosis

et al. 2016

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“…Ano6 has attracted large attention due to its properties as a Ca 2+ -activated phospholipid scramblase and Ca 2+ -activated Cl − channel (for review see Kunzelmann et al [26]). Despite earlier controversies arguing against the role of Ano6 as a Cl − permeable ion channel [54], it has now been clearly shown by several independent groups, to produce a large conductance Cl − permeable channel activated by strong (≥10 μM) increase in intracellular Ca 2+ [15,21,30,31,46,49]. Moreover, Ano6 has been shown to be activated during cellular volume regulation and apoptotic cell death [1,20,21,31].…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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“…Although TMEM16A and TMEM16B are clearly Ca 2+ -activated Cl -channels (Caputo et al, 2008;Schroeder et al, 2008;Yang et al, 2008), the physiological functions of other members of the TMEM16 family have been dubious (Duran and Hartzell, 2011). For example, although TMEM16F certainly is a phospholipid scramblase (Suzuki et al, 2010), it has also been reported to be a nonselective cation channel Adomaviciene et al, 2013) and various types of Cl -channel (Almaç a et al, 2009;Martins et al, 2011;Szteyn et al, 2012;Grubb et al, 2013;Shimizu et al, 2013;Juul et al, 2014). The crystal structure of nhTMEM16 does not reveal an obvious alternative pathway for ion permeation through the bilayer other than the path taken by phospholipids and we have proposed that the ion conductance of TMEM16F represents a leak of ions through the aqueduct that occurs during lipid scrambling (Yu et al, 2015).…”

Section: Mechanisms Of Ion Transportmentioning

confidence: 99%

Lipids and Ions Traverse the Membrane by the Same Physical Pathway in the nhTMEM16 Scramblase

Jiang

Hartzell

et al. 2018

Biophysical Journal

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From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca 2+ binding stimulates its open conformation by altering the structure of transmembrane helices that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl -channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca 2+ -activated Cl -channel convert it into a robust scramblase.

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TMEM16F (Anoctamin 6), an anion channel of delayed Ca2+ activation

Cited by 109 publications

References 61 publications

Cl− channels in apoptosis

Cl− channels in apoptosis

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

Lipids and Ions Traverse the Membrane by the Same Physical Pathway in the nhTMEM16 Scramblase

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