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J. Biol. Chem., Vol. 276, Issue 11, 8306-8313, March 16, 2001
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From the Programme in Cell Biology and Genetics at the Hospital for
Sick Children and the Departments of Physiology and Molecular Genetics
at the University of Toronto, Toronto, M5G 1X8 Ontario, Canada
It has been previously determined that ClC-2, a
member of the ClC chloride channel superfamily, is expressed in certain
epithelial tissues. These findings fueled speculation that ClC-2 can
compensate for impaired chloride transport in epithelial tissues
affected by cystic fibrosis and lacking the cystic fibrosis
transmembrane conductance regulator. However, direct evidence linking
ClC-2 channel expression to epithelial chloride secretion was lacking. In the present studies, we show that ClC-2 transcripts and protein are
present endogenously in the Caco-2 cell line, a cell line that models
the human small intestine. Using an antisense strategy we show that
ClC-2 contributes to native chloride currents in Caco-2 cells measured
by patch clamp electrophysiology. Antisense ClC-2-transfected
monolayers of Caco-2 cells exhibited less chloride secretion (monitored
as iodide efflux) than did mock transfected monolayers, providing the
first direct molecular evidence that ClC-2 can contribute to chloride
secretion by the human intestinal epithelium. Further, examination of
ClC-2 localization by confocal microscopy revealed that ClC-2
contributes to secretion from a unique location in this epithelium,
from the apical aspect of the tight junction complex. Hence, these
studies provide the necessary rationale for considering ClC-2 as a
possible therapeutic target for diseases affecting intestinal chloride
secretion such as cystic fibrosis.
ClC-2 Contributes to Native Chloride Secretion by a Human
Intestinal Cell Line, Caco-2*
§,¶,
*
This work was funded by a National Institutes of Health
grant (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.
These authors contributed equally to this work.
§
Recipient of a Fellowship award from the Canadian Cystic Fibrosis Foundation.
¶
Recipient of a Studentship award from the Canadian Cystic
Fibrosis Foundation.
To whom correspondence should be addressed: Research Inst.,
Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G
1X8, Canada. Tel.: 416-813-5981; Fax: 416-813-5028; E-mail: bear@ sickkids.on.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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