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J. Biol. Chem., Vol. 277, Issue 1, 566-574, January 4, 2002
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From the Program in Structural Biology, Research Institute,
Hospital for Sick Children, Toronto M5S 1G8, Canada
Cystic fibrosis (CF) causing mutations in the
cystic fibrosis transmembrane conductance regulator (CFTR) lead to
mislocalization of CFTR protein from the brush border membrane of
epithelial tissues and/or its dysfunction as a chloride channel. In
initial reports, it was proposed that certain channels from the ClC
family of chloride channels may provide compensatory or alternative
pathways for epithelial chloride secretion in tissues from cystic
fibrosis patients. In the present work, we provide the first evidence
that ClC-4 protein is functionally expressed on the surface of the intestinal epithelium and hence, is appropriately localized to act as a
therapeutic target in this CF-affected tissue. We show using confocal
and electron microscopy that ClC-4 co-localizes with CFTR in the brush
border membrane of the epithelium lining intestinal crypts in mouse and
human tissues. In Caco-2 cells, a cell line thought to model human
enterocytes, ClC-4 protein is expressed on the cell surface and also
partially co-localizes with EEA1 and transferrin, marker molecules of
early and recycling endosomes, respectively. Hence, like CFTR, ClC-4
may cycle between the plasma membrane and endosomal compartment.
Furthermore, we show that ClC-4 functions as a chloride channel on the
surface of these epithelial cells as antisense ClC-4 cDNA
expression reduced the amplitude of endogenous chloride currents by
50%. These studies provide the first evidence that ClC-4 is
endogenously expressed and may be functional in the brush border
membrane of enterocytes and hence should be considered as a candidate
channel to provide an alternative pathway for chloride secretion in the
gastrointestinal tract of CF patients.
The Chloride Channel ClC-4 Co-localizes with Cystic Fibrosis
Transmembrane Conductance Regulator and May Mediate Chloride
Flux across the Apical Membrane of Intestinal Epithelia*
,
*
This work was supported in part by operating grants awarded
by the Canadian Institutes of Health and the National Institutes of
Health (to C. E. B.).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.
Supported by a fellowship from The Canadian Cystic Fibrosis Foundation.
§
To whom correspondence should be addressed: Program in Structural
Biology, Research Institute, Hospital for Sick Children, 555 University
Ave., Toronto, Canada. Tel.: 416-813-5981; Fax: 416-813-5028; E-mail:
bear@sickkids.on.ca.
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