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Editors' Choice:
Chloride Channel Clinched
Katrina L. Kelner (28 October 2008)
Sci. Signal. 1 (43), ec371-ec371. [DOI: 10.1126/scisignal.143ec371]
Abstract »  
Posted E-Letters:

Chloride Currents: Don't Forget ClC-3

While there is much justified excitement concerning the identification of TMEM16A as a calcium-activated chloride channel (1, 2), I would like to draw attention to the existence of a completely different protein that makes substantial contributions to the transmembrane chloride currents that drive "cell excitability and fluid secretion", as well as many other physiological activities (3). These particular chloride currents also owe their activation to elevations in cytosolic calcium, but indirectly, through the activity of calcium calmodulin kinase II (CaMKII) (4); these chloride currents are also of biological interest because they are inhibited in a receptor-dependent manner by a specific member of the inositol phosphate signaling family (3-6). It is ClC-3 that is responsible for these chloride currents (3); the electrophysiological characteristics of the CaMKII-activated, ClC-3 driven whole-cell currents mirror those of native kinase-activated chloride currents (3-7). The identification of TMEM16A is important, but it's not, as you argue, the "long-sought primary carrier", and neither does its discovery "clinch" the chloride channel field.


  1. A. Caputo, E. Caci, L. Ferrera, N. Pedemonte, C. Barsanti, E. Sondo, U. Pfeffer, R. Ravazzolo, O. Zegarra-Moran, L. J. Galietta, TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity Science 322, 590-594 (2008). [Abstract (Virtual Journal)] [Full Text (Virtual Journal)]
  2. Y. D. Yang, H. Cho, J. Y. Koo, M. H. Tak, Y. Cho, W. S. Shim, S. P. Park, J. Lee, B. Lee, B. M. Kim, R. Raouf, Y. K. Shin, U. Oh, TMEM16A confers receptor-activated calcium-dependent chloride conductance .Nature 455, 1210-1215 (2008). [PubMed Abstract]
  3. J. Mitchell, X. Wang, G. Zhang, M. Gentzsch, D. J. Nelson, S. B. Shears, An expanded biological repertoire for Ins(3,4,5,6)P4 through its modulation of ClC-3 function. Curr Biol. 18 1600-1605 (2008). [PubMed Abstract]
  4. P. Huang, J. Liu, A. Di, N. C. Robinson, M. W. Musch, M. A. Kaetzel, D. J. Nelson, Regulation of human CLC-3 channels by multifunctional Ca2+/calmodulin-dependent protein kinase. J. Biol. Chem. 276 20093-20100 (2001). [Abstract (Virtual Journal)] [Full Text (Virtual Journal)]
  5. L. Yang, J. Reece, S. E. Gabriel, S. B. Shears, Apical localization of ITPK1 enhances its ability to be a modifier gene product in a murine tracheal cell model of cystic fibrosis. J. Cell Sci. 119, 1320-1328 (2006). [Abstract (Virtual Journal)] [Full Text (Virtual Journal)]
  6. M. W. Y. Ho, M. A. Kaetzel, D. L. Armstrong, S. B. Shears, Regulation of a Human Chloride Channel. A PARADIGM FOR INTEGRATING INPUT FROM CALCIUM, TYPE II CALMODULIN-DEPENDENT PROTEIN KINASE, AND INOSITOL 3,4,5,6-TETRAKISPHOSPHATE.J. Biol. Chem. 276, 18673-18680 (2001). [Abstract (Virtual Journal)] [Full Text (Virtual Journal)]
  7. X. Q. Wang, L. V. Deriy, S. Foss, P. Huang, F. S. Lamb, M. A. Kaetzel, V. Bindokas, J. D. Marks, D. J. Nelson, CLC-3 channels modulate excitatory synaptic transmission in hippocampal neurons. Neuron 52, 321-333 (2006). [PubMed Abstract]

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