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J. Biol. Chem., Vol. 277, Issue 10, 7676-7683, March 8, 2002
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From the The stimulative effect of glucocorticoids on
intestinal salt and water absorption has been known for more than two
decades. However, molecular mechanisms underlying this activation
remain elusive. Previous studies showed that methylprednisolone
specifically increased Na+/H+ exchanger
isoform (NHE) 3 mRNA in ileum and kidney without affecting NHE1
mRNA levels. These results suggest that glucocorticoids activate NHE3 activity by induction of NHE3 transcripts. We recently found in
PS120 and opossum kidney cells that chronic incubation with dexamethasone activated NHE3 independent of gene induction, indicating that the transcriptional activation may not be the only determining factor in the NHE3 activation. Furthermore, dexamethasone activated NHE3 activity only in the presence of a NHE3 regulatory protein, NHERF2, which was previously shown to confer cAMP-dependent
inhibition of NHE3. This activation of NHE3 could not be duplicated by
NHERF1. We identified serum- and glucocorticoid-induced protein kinase, SGK1, as the protein interacting with PDZ domains of NHERF2 to regulate
NHE3 activity. The expression of SGK1 enhanced NHE3 transport in PS120
fibroblasts. In addition, the "kinase-dead" SGK1 blocked activation
of NHE3 by dexamethasone in opossum kidney cells. These data
demonstrated that glucocorticoid activation of NHE3 requires the
activation of SGK1 and the presence of NHERF2 acting as a scaffold protein.
Glucocorticoid Activation of Na+/H+
Exchanger Isoform 3 Revisited
THE ROLES OF SGK1 AND NHERF2*
§,, and Department of Medicine, Gastroenterology
Division, The Johns Hopkins University School of Medicine, Baltimore,
Maryland 21205 and the ¶ Institute of Physiology, University of
Tübingen, D-72076 Tübingen, Germany
*
This work was supported in part by National Institutes of
Health Grant DK-44484 and Deutsche Forschungsgemeinschaft Grant LLa
315/4-5.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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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