Identification and Functional Characterization of TMEM16A, a Ca2+-activated Cl− Channel Activated by Extracellular Nucleotides, in Biliary Epithelium

Dutta, Amal K.; Khimji, Al Karim; Kresge, Charles; Bugde, Abhijit; Dougherty, Michael P.; Esser, Victoria; Ueno, Yoshiyuki; Glaser, Shannon; Alpini, Gianfranco; Rockey, Don C.; Feranchak, Andrew P.

doi:10.1074/jbc.m110.164970

Cited by 95 publications

(109 citation statements)

References 47 publications

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“…This approach resulted in marked inhibition of Ca 2+ -dependent anion transport (Caputo et al 2008). Many other investigators confirmed these results by transfecting or silencing TMEM16A in various cell models (Davis et al 2010;Romanenko et al 2010;Dutta et al 2011). The link between TMEM16A and Cl − transport was further strengthened following the generation of a knockout mouse.…”

Section: Tmem16a and Tmem16b Proteins As Caccssupporting

confidence: 56%

The anoctamin family: TMEM16A and TMEM16B as calcium‐activated chloride channels

Scudieri

Sondo

Ferrera

et al. 2011

Experimental Physiology

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The Ca2+ -activated Cl − channels (CaCCs) are involved in a variety of physiological functions, such as transepithelial anion transport, smooth muscle contraction and olfaction. Recently, the question of the molecular identity of CaCCs has apparently been resolved with the identification of TMEM16A protein (also known as anoctamin-1). Expression of TMEM16A is associated with the appearance of Ca 2+ -and voltage-dependent Cl − currents with properties similar to those of native CaCCs. The putative structure of TMEM16A consists of eight transmembrane domains, with both the amino-and the carboxy-terminus protruding in the cytosol. TMEM16A is also characterized by the existence of different protein variants generated by alternative splicing. A close paralogue of TMEM16A, TMEM16B (anoctamin-2), is also associated with CaCC activity, although with different properties. The TMEM16B-dependent channels require higher intracellular Ca 2+ concentrations and have faster activation and deactivation kinetics. Expression of other anoctamins is devoid of detectable channel activity. These proteins, such as TMEM16F (anoctamin-6), may have different functions.

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Section: Tmem16a and Tmem16b Proteins As Caccssupporting

confidence: 56%

The anoctamin family: TMEM16A and TMEM16B as calcium‐activated chloride channels

Scudieri

Sondo

Ferrera

et al. 2011

Experimental Physiology

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“…Loss of expression of Ano 1 in knockout animals leads to multiple defects in epithelial organs such as airways, salivary glands, pancreatic glands, hepatobiliary tract, and large intestine [23,33,59,82,93,94,114,121]. More recent studies show the importance of Ano 1 in Cajal pacemaker and smooth muscle cells of airways, [20,36,44,65,122].…”

Section: Anoctamins In Health and Diseasementioning

confidence: 94%

Anoctamins

Kunzelmann

Tian

Martins

et al. 2011

Pflugers Arch - Eur J Physiol

104

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Endogenous Ca(2+)-activated Cl(-) channels (CaCC) demonstrate biophysical and pharmacological properties that are well represented in cells overexpressing anoctamin 1 (Ano 1, TMEM16A), a protein that has been identified recently as CaCC. Proteins of the anoctamin family (anoctamin 1-10, TMEM16A-K) are widely expressed. The number of reports demonstrating their physiological and clinical relevance is quickly rising. Anoctamins gain additional interest through their potential role in cell volume regulation and malignancy. Available data suggest that Ano 1 forms stable dimers and probably liaise with accessory proteins such as calmodulin or other anoctamins. In order to understand how anoctamins produce Ca(2+)-activated Cl(-) currents, it will be necessary to obtain better insight into their molecular structure, interactions with partner proteins, and mode of activation.

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“…Thus it appears that the TMEM16F-dependent CaCC is distinct from TMEM16A-and TMEM16B-dependent CaCCs in its Ca 2ϩ sensitivity. Native CaCCs in a variety of cells have been reported to show different sensitivities to intracellular Ca 2ϩ that fall in the nanomolar to micromolar range (10) (8,29). Considering that TMEM16F is ubiquitously expressed (25), it would be interesting to investigate how the level of TMEM16F expression affects the Ca 2ϩ sensitivity of endogenous CaCCs in different cell types.…”

Section: Tmem16f and Tmem16k Do Not Underlie Vsor Activitymentioning

confidence: 99%

TMEM16F is a component of a Ca²⁺-activated Cl⁻ channel but not a volume-sensitive outwardly rectifying Cl⁻ channel

Shimizu

Iehara

Sato

et al. 2013

American Journal of Physiology-Cell Physiology

115

157

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TMEM16 (transmembrane protein 16) proteins, which possess eight putative transmembrane domains with intracellular NH2- and COOH-terminal tails, are thought to comprise a Cl− channel family. The function of TMEM16F, a member of the TMEM16 family, has been greatly controversial. In the present study, we performed whole cell patch-clamp recordings to investigate the function of human TMEM16F. In TMEM16F-transfected HEK293T cells but not TMEM16K- and mock-transfected cells, activation of membrane currents with strong outward rectification was found to be induced by application of a Ca2+ ionophore, ionomycin, or by an increase in the intracellular free Ca2+ concentration. The free Ca2+ concentration for half-maximal activation of TMEM16F currents was 9.6 μM, which is distinctly higher than that for TMEM16A/B currents. The outwardly rectifying current-voltage relationship for TMEM16F currents was not changed by an increase in the intracellular Ca2+ level, in contrast to TMEM16A/B currents. The Ca2+-activated TMEM16F currents were anion selective, because replacing Cl− with aspartate− in the bathing solution without changing cation concentrations caused a positive shift of the reversal potential. The anion selectivity sequence of the TMEM16F channel was I− > Br− > Cl− > F− > aspartate−. Niflumic acid, a Ca2+-activated Cl− channel blocker, inhibited the TMEM16F-dependent Cl− currents. Neither overexpression nor knockdown of TMEM16F affected volume-sensitive outwardly rectifying Cl− channel (VSOR) currents activated by osmotic swelling or apoptotic stimulation. These results demonstrate that human TMEM16F is an essential component of a Ca2+-activated Cl− channel with a Ca2+ sensitivity that is distinct from that of TMEM16A/B and that it is not related to VSOR activity.

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Identification and Functional Characterization of TMEM16A, a Ca2+-activated Cl− Channel Activated by Extracellular Nucleotides, in Biliary Epithelium

Abstract: Cl؊ channels in the apical membrane of biliary epithelial

Cited by 95 publications

References 47 publications

The anoctamin family: TMEM16A and TMEM16B as calcium‐activated chloride channels

The anoctamin family: TMEM16A and TMEM16B as calcium‐activated chloride channels

Anoctamins

TMEM16F is a component of a Ca²⁺-activated Cl⁻ channel but not a volume-sensitive outwardly rectifying Cl⁻ channel

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Identification and Functional Characterization of TMEM16A, a Ca2+-activated Cl− Channel Activated by Extracellular Nucleotides, in Biliary Epithelium

Abstract: Cl؊ channels in the apical membrane of biliary epithelial

Cited by 95 publications

References 47 publications

The anoctamin family: TMEM16A and TMEM16B as calcium‐activated chloride channels

The anoctamin family: TMEM16A and TMEM16B as calcium‐activated chloride channels

Anoctamins

TMEM16F is a component of a Ca2+-activated Cl− channel but not a volume-sensitive outwardly rectifying Cl− channel

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About

TMEM16F is a component of a Ca²⁺-activated Cl⁻ channel but not a volume-sensitive outwardly rectifying Cl⁻ channel