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Science 322 (5901): 590-594

Copyright © 2008 by the American Association for the Advancement of Science

TMEM16A, A Membrane Protein Associated with Calcium-Dependent Chloride Channel Activity

Antonella Caputo,1 Emanuela Caci,1 Loretta Ferrera,1 Nicoletta Pedemonte,2 Cristina Barsanti,1 Elvira Sondo,1 Ulrich Pfeffer,3 Roberto Ravazzolo,1 Olga Zegarra-Moran,1 Luis J. V. Galietta1,2*

Abstract: Calcium-dependent chloride channels are required for normal electrolyte and fluid secretion, olfactory perception, and neuronal and smooth muscle excitability. The molecular identity of these membrane proteins is still unclear. Treatment of bronchial epithelial cells with interleukin-4 (IL-4) causes increased calcium-dependent chloride channel activity, presumably by regulating expression of the corresponding genes. We performed a global gene expression analysis to identify membrane proteins that are regulated by IL-4. Transfection of epithelial cells with specific small interfering RNA against each of these proteins shows that TMEM16A, a member of a family of putative plasma membrane proteins with unknown function, is associated with calcium-dependent chloride current, as measured with halide-sensitive fluorescent proteins, short-circuit current, and patch-clamp techniques. Our results indicate that TMEM16A is an intrinsic constituent of the calcium-dependent chloride channel. Identification of a previously unknown family of membrane proteins associated with chloride channel function will improve our understanding of chloride transport physiopathology and allow for the development of pharmacological tools useful for basic research and drug development.

1 Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova 16148, Italy.
2 Centro di Biotecnologie Avanzate, Genova 16132, Italy.
3 National Cancer Research Institute, Genova 16132, Italy.

* To whom correspondence should be addressed. E-mail: galietta{at}

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Science Translational Medicine 3, 74ra24
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Calmodulin-dependent activation of the epithelial calcium-dependent chloride channel TMEM16A.
Y. Tian, P. Kongsuphol, M. Hug, J. Ousingsawat, R. Witzgall, R. Schreiber, and K. Kunzelmann (2011)
FASEB J 25, 1058-1068
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Activation of the basolateral membrane Cl- conductance essential for electrogenic K+ secretion suppresses electrogenic Cl- secretion.
Q. He, S. T. Halm, J. Zhang, and D. R. Halm (2011)
Exp Physiol 96, 305-316
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TMEM16A(a)/anoctamin-1 Shares a Homodimeric Architecture with CLC Chloride Channels.
G. Fallah, T. Romer, S. Detro-Dassen, U. Braam, F. Markwardt, and G. Schmalzing (2011)
Mol. Cell. Proteomics 10, M110.004697
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TMEM16A Inhibitors Reveal TMEM16A as a Minor Component of Calcium-activated Chloride Channel Conductance in Airway and Intestinal Epithelial Cells.
W. Namkung, P.-W. Phuan, and A. S. Verkman (2011)
J. Biol. Chem. 286, 2365-2374
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Characterization of the Oligomeric Structure of the Ca2+-activated Cl- Channel Ano1/TMEM16A.
J. T. Sheridan, E. N. Worthington, K. Yu, S. E. Gabriel, H. C. Hartzell, and R. Tarran (2011)
J. Biol. Chem. 286, 1381-1388
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Identification and Functional Characterization of TMEM16A, a Ca2+-activated Cl- Channel Activated by Extracellular Nucleotides, in Biliary Epithelium.
A. K. Dutta, A.-k. Khimji, C. Kresge, A. Bugde, M. Dougherty, V. Esser, Y. Ueno, S. S. Glaser, G. Alpini, D. C. Rockey, et al. (2011)
J. Biol. Chem. 286, 766-776
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Location of Release Sites and Calcium-Activated Chloride Channels Relative to Calcium Channels at the Photoreceptor Ribbon Synapse.
A. J. Mercer, K. Rabl, G. E. Riccardi, N. C. Brecha, S. L. Stella Jr, and W. B. Thoreson (2011)
J Neurophysiol 105, 321-335
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TMEM16A Protein: A New Identity for Ca2+-Dependent Cl- Channels.
L. Ferrera, A. Caputo, and L. J. V. Galietta (2010)
Physiology 25, 357-363
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Allergic airway inflammation induces a pro-secretory epithelial ion transport phenotype in mice.
P. Anagnostopoulou, L. Dai, J. Schatterny, S. Hirtz, J. Duerr, and M. A. Mall (2010)
Eur. Respir. J. 36, 1436-1447
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Inhibition of Ca2+-activated Cl- channels by gallotannins as a possible molecular basis for health benefits of red wine and green tea.
W. Namkung, J. R. Thiagarajah, P.-W. Phuan, and A. S. Verkman (2010)
FASEB J 24, 4178-4186
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