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J. Biol. Chem., Vol. 277, Issue 13, 11090-11096, March 29, 2002
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From the Allosteric control of
Na+/H+ exchange by intracellular protons
ensures rapid and accurate regulation of the intracellular pH. Although
this allosteric effect was heretofore thought to occur almost
instantaneously, we report here the occurrence of a slower secondary
activation of the epithelial Na+/H+ exchanger
(NHE)-3 isoform. This slow activation mode developed over the course of
minutes and was unique to NHE3 and the closely related isoform NHE5,
but was not observed in NHE1 or NHE2. Activation of NHE3 was not due to
increased density of exchangers at the cell surface, nor was it
accompanied by detectable changes in phosphorylation. The association
of NHE3 with the cytoskeleton, assessed by its retention in the
detergent-insoluble fraction, was similarly unaffected by
acidification. In contrast to the slow progressive activation elicited
by acidification, deactivation occurred very rapidly upon restoration
of the physiological pH. We propose that NHE3 undergoes a slow
pH-dependent transition from a less active to a more active
state, likely by changing its conformation or state of association.
A Slow pH-dependent Conformational Transition
Underlies a Novel Mode of Activation of the Epithelial
Na+/H+ Exchanger-3 Isoform*
,§,,
,
Cell Biology Program, Hospital for Sick
Children Research Institute, Toronto, Ontario M5G 1X8, Canada, the
¶ Department of Physiology, McGill University, Montreal, Quebec
H3G 1Y6, Canada, and the ** Laboratory of Cardiovascular
Science, Gerontology Research Center, NIA, National Institutes of
Health, Baltimore, Maryland 21224
*
This work was supported in part by the Canadian Institutes
of Health Research and the Kidney Foundation of Canada.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.
Investigator of the Canadian Institutes of Health Research.
International Scholar of the Howard Hughes Medical Institute;
current holder of the Pitblado Chair in Cell Biology at the Hospital
for Sick Children; and cross-appointed to the Department of
Biochemistry, University of Toronto. To whom correspondence should be
addressed: Cell Biology Program, Hospital for Sick Children Research
Inst., 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.:
416-813-5727; Fax: 416-813-5028; E-mail: sga@sickkids.ca.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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