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Originally published In Press as doi:10.1074/jbc.M111482200 on December 28, 2001
J. Biol. Chem., Vol. 277, Issue 11, 8928-8933, March 15, 2002
Genistein Restores Functional Interactions between F508-CFTR
and ENaC in Xenopus Oocytes*
Laurence
Suaud §¶,
Jinqing
Li ¶,
Qinshi
Jiang ¶,
Ronald C.
Rubenstein ** , and
Thomas R.
Kleyman§§¶¶
From the Division of Pulmonary Medicine, Children's
Hospital of Philadelphia, Departments of Medicine and
** Pediatrics, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania, 19104 and
§§ Renal-Electrolyte Division, Department of
Medicine, University of Pittsburgh,
Pittsburgh, Pennsylvania 15261
The cystic fibrosis transmembrane conductance
regulator (CFTR), in addition to its Cl channel
properties, has regulatory interactions with other epithelial ion
channels including the epithelial Na+ channel (ENaC). Both
the open probability and surface expression of wild type CFTR
Cl channels are increased significantly when CFTR is
co-expressed in Xenopus oocytes with   -ENaC,
and conversely, the activity of ENaC is inhibited following wild type
CFTR activation. Using the Xenopus oocyte expression
system, a lack of functional regulatory interactions between
F508-CFTR and ENaC was observed following activation of F508-CFTR
by forskolin and isobutylmethylxanthine (IBMX). Whole cell currents in
oocytes expressing ENaC alone decreased in response to genistein but
increased in response to a combination of forskolin and IBMX followed
by genistein. In contrast, ENaC currents in oocytes co-expressing ENaC
and F508-CFTR remained stable following stimulation with
forskolin/IBMX/genistein. Furthermore, co-expression of F508-CFTR
with ENaC enhanced the forskolin/IBMX/genistein-mediated activation of
F508-CFTR. Our data suggest that genistein restores regulatory
interactions between F508-CFTR and ENaC and that combinations of
protein repair agents, such as 4-phenylbutyrate and genistein, may
be necessary to restore F508-CFTR function in
vivo.
*
This work was supported by Grants DK56305 and DK58046 from
the National Institutes of Health (to T. R. K. and to R. C. R., respectively).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.
§
Recipient of a postdoctoral fellowship award from the
Pennsylvania/Delaware Chapter of the American Heart Association.
¶
Recipient of a postdoctoral fellowship award from the Cystic
Fibrosis Foundation.

Recipient of a Cystic Fibrosis Foundation Leroy Matthews
Individual Physician Scientist Award.
¶¶
To whom correspondence should be addressed:
Renal-Electrolyte Division, A919 Scaife Hall, 3550 Terrace St.,
Pittsburgh, PA 15261. Tel.: 412-647-3121; Fax: 412-648-9166; E-mail:
kleyman@pitt.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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