Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Biol. Chem. 276 (22): 18673-18680

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of a Human Chloride Channel

Melisa W. Y. HoDagger §, Marcia A. Kaetzel, David L. Armstrong||, and Stephen B. ShearsDagger

From the Dagger  Inositide Signaling and || Membrane Signaling Groups, Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709 and the  Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0576

We have studied the regulation of Ca2+-dependent chloride (ClCa) channels in a human pancreatoma epithelial cell line (CFPAC-1), which does not express functional cAMP-dependent cystic fibrosis transmembrane conductance regulator chloride channels. In cell-free patches from these cells, physiological Ca2+ concentrations activated a single class of 1-picosiemens Cl--selective channels. The same channels were also stimulated by a purified type II calmodulin-dependent protein kinase (CaMKII), and in cell-attached patches by purinergic agonists. In whole-cell recordings, both Ca2+- and CaMKII-dependent mechanisms contributed to chloride channel stimulation by Ca2+, but the CaMKII-dependent pathway was selectively inhibited by inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4). This inhibitory effect of Ins(3,4,5,6)P4 on ClCa channel stimulation by CaMKII was reduced by raising [Ca2+] and prevented by inhibition of protein phosphatase activity with 100 nM okadaic acid. These data provide a new context for understanding the physiological relevance of Ins(3,4,5,6)P4 in the longer term regulation of Ca2+-dependent Cl- fluxes in epithelial cells.

* This work was supported in part by National Institutes of Health Grant DK 46433 and a grant from the Caroline Spahn Halfter Trust Genetic Research Fund.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed. Tel.: 919-541-2630; Fax: 919-541-0559; E-mail:

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Structure and Function of TMEM16 Proteins (Anoctamins).
N. Pedemonte and L. J. V. Galietta (2014)
Physiol Rev 94, 419-459
   Abstract »    Full Text »    PDF »
Depolarization-induced depression of inhibitory transmission in cerebellar Purkinje cells.
H. Satoh, L. Qu, H. Suzuki, and F. Saitow (2013)
PHY2 1, e00061
   Abstract »    Full Text »    PDF »
Functional Regulation of ClC-3 in the Migration of Vascular Smooth Muscle Cells.
S. B. Ganapathi, S.-G. Wei, A. Zaremba, F. S. Lamb, and S. B. Shears (2013)
Hypertension 61, 174-179
   Abstract »    Full Text »    PDF »
CaMKII inhibition hyperpolarizes membrane and blocks nitrergic IJP by closing a Cl- conductance in intestinal smooth muscle.
X.-D. He and R. K. Goyal (2012)
Am J Physiol Gastrointest Liver Physiol 303, G240-G246
   Abstract »    Full Text »    PDF »
Regulation of inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) by reversible lysine acetylation.
C. Zhang, P. W. Majerus, and M. P. Wilson (2012)
PNAS 109, 2290-2295
   Abstract »    Full Text »    PDF »
Molecular Mechanism of Pancreatic and Salivary Gland Fluid and HCOFormula Secretion.
M. G. Lee, E. Ohana, H. W. Park, D. Yang, and S. Muallem (2012)
Physiol Rev 92, 39-74
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Spatial and temporal integration of signalling networks regulating pollen tube growth.
L. Zonia (2010)
J. Exp. Bot.
   Abstract »    Full Text »    PDF »
Regulation of TMEM16A Chloride Channel Properties by Alternative Splicing.
L. Ferrera, A. Caputo, I. Ubby, E. Bussani, O. Zegarra-Moran, R. Ravazzolo, F. Pagani, and L. J. V. Galietta (2009)
J. Biol. Chem. 284, 33360-33368
   Abstract »    Full Text »    PDF »
Bestrophin-1 Enables Ca2+-activated Cl- Conductance in Epithelia.
R. Barro Soria, M. Spitzner, R. Schreiber, and K. Kunzelmann (2009)
J. Biol. Chem. 284, 29405-29412
   Abstract »    Full Text »    PDF »
{beta}1-Adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction.
B. Yoo, A. Lemaire, S. Mangmool, M. J. Wolf, A. Curcio, L. Mao, and H. A. Rockman (2009)
Am J Physiol Heart Circ Physiol 297, H1377-H1386
   Abstract »    Full Text »    PDF »
Single Cl- Channels Activated by Ca2+ in Drosophila S2 Cells Are Mediated By Bestrophins.
L.-T. Chien, Z.-R. Zhang, and H. C. Hartzell (2006)
J. Gen. Physiol. 128, 247-259
   Abstract »    Full Text »    PDF »
Annexin A4 Self-Association Modulates General Membrane Protein Mobility in Living Cells.
A. Piljic and C. Schultz (2006)
Mol. Biol. Cell 17, 3318-3328
   Abstract »    Full Text »    PDF »
Apical localization of ITPK1 enhances its ability to be a modifier gene product in a murine tracheal cell model of cystic fibrosis.
L. Yang, J. Reece, S. E. Gabriel, and S. B. Shears (2006)
J. Cell Sci. 119, 1320-1328
   Abstract »    Full Text »    PDF »
Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia.
M. Moody, C. Pennington, C. Schultz, R. Caldwell, C. Dinkel, M. W. Rossi, S. McNamara, J. Widdicombe, S. Gabriel, and A. E. Traynor-Kaplan (2005)
Am J Physiol Cell Physiol 289, C512-C520
   Abstract »    Full Text »    PDF »
Modeling action potential generation and propagation in NRK fibroblasts.
J. J. Torres, L. N. Cornelisse, E. G. A. Harks, W. P. M. van Meerwijk, A. P. R. Theuvenet, and D. L. Ypey (2004)
Am J Physiol Cell Physiol 287, C851-C865
   Abstract »    Full Text »    PDF »
Identification of an N-terminal amino acid of the CLC-3 chloride channel critical in phosphorylation-dependent activation of a CaMKII-activated chloride current.
N. C. Robinson, P. Huang, M. A. Kaetzel, F. S. Lamb, and D. J. Nelson (2004)
J. Physiol. 556, 353-368
   Abstract »    Full Text »    PDF »
Kinetics and regulation of a Ca2+-activated Cl- conductance in mouse renal inner medullary collecting duct cells.
S. H. Boese, O. Aziz, N. L. Simmons, and M. A. Gray (2004)
Am J Physiol Renal Physiol 286, F682-F692
   Abstract »    Full Text »    PDF »
Osmotically Induced Cell Swelling versus Cell Shrinking Elicits Specific Changes in Phospholipid Signals in Tobacco Pollen Tubes.
L. Zonia and T. Munnik (2004)
Plant Physiology 134, 813-823
   Abstract »    Full Text »    PDF »
Oscillatory Chloride Efflux at the Pollen Tube Apex Has a Role in Growth and Cell Volume Regulation and Is Targeted by Inositol 3,4,5,6-Tetrakisphosphate.
L. Zonia, S. Cordeiro, J. Tupy, and J. A. Feijo (2002)
PLANT CELL 14, 2233-2249
   Abstract »    Full Text »    PDF »
Inositol 3,4,5,6-Tetrakisphosphate Inhibits Insulin Granule Acidification and Fusogenic Potential.
E. Renstrom, R. Ivarsson, and S. B. Shears (2002)
J. Biol. Chem. 277, 26717-26720
   Abstract »    Full Text »    PDF »
Molecular Structure and Physiological Function of Chloride Channels.
T. J. Jentsch, V. Stein, F. Weinreich, and A. A. Zdebik (2002)
Physiol Rev 82, 503-568
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882