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J. Biol. Chem., Vol. 277, Issue 26, 23604-23611, June 28, 2002
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From the ClC-2 is localized to the apical membranes of
secretory epithelia where it has been hypothesized to play a role in
fluid secretion. Although ClC-2 is clearly the inwardly rectifying
anion channel in several tissues, the molecular identity of the
hyperpolarization-activated Cl
Loss of Hyperpolarization-activated Cl
Current in
Salivary Acinar Cells from Clcn2 Knockout Mice*
§,¶,§,,,
,, and§
Center for Oral Biology, Aab Institute of
Biomedical Sciences, the § Eastman Department of
Dentistry, the ** Department of Laboratory Animal
Medicine, and the ¶ Department of Pharmacology and
Physiology, University of Rochester Medical Center, Rochester, New
York 14642 and the Department of Molecular Genetics,
Biochemistry, and Microbiology, University of Cincinnati College of
Medicine, Cincinnati, Ohio 45267
current in other
organs, including the salivary gland, is currently unknown. To
determine the nature of the hyperpolarization-activated Cl current and to examine the role of ClC-2 in salivary
gland function, a mouse line containing a targeted disruption of the
Clcn2 gene was generated. The resulting homozygous
Clcn2/ mice lacked detectable
hyperpolarization-activated chloride currents in parotid acinar cells
and, as described previously, displayed postnatal degeneration of the
retina and testis. The magnitude and biophysical characteristics of the
volume- and calcium-activated chloride currents in these cells were
unaffected by the absence of ClC-2. Although ClC-2 appears to
contribute to fluid secretion in some cell types, both the initial and
sustained salivary flow rates were normal in
Clcn2/ mice following in vivo
stimulation with pilocarpine, a cholinergic agonist. In addition, the
electrolytes and protein contents of the mature secretions were normal.
Because ClC-2 has been postulated to contribute to cell volume control,
we also examined regulatory volume decrease following cell swelling.
However, parotid acinar cells from Clcn2/
mice recovered volume with similar efficiency to wild-type littermates. These data demonstrate that ClC-2 is the hyperpolarization-activated Cl channel in salivary acinar cells but is not essential
for maximum chloride flux during stimulated secretion of saliva or
acinar cell volume regulation.
*
This work was supported in part by National Institutes of
Health Grants DE09692 and DE13539 (to J. E. M.) and DK50594 (to G. E. S.).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: Center for Oral
Biology, Aab Institute of Biomedical Sciences, University of Rochester Medical Center, Box 611, 601 Elmwood Ave., Rochester, NY
14642. Tel.: 585-275-3444; Fax: 585-506-0190; E-mail:
james_melvin@urmc.rochester.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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