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J Biol Chem, Vol. 274, Issue 53, 37551-37558, December 31, 1999
From the Trafficking of the
Na+/H+ exchanger isoform 3 (NHE3) between
sub-apical vesicles and apical membrane of epithelial cells is a
suggested mechanism of regulation of NHE3 activity. When epitope-tagged NHE3 was stably expressed in NHE-deficient Chinese hamster ovary cells,
a sizable fraction was found in recycling endosomes. This system was
used to analyze the mechanism of endocytosis of NHE3. Immunofluorescence and radiolabeling experiments showed that inhibition of clathrin-mediated endocytosis using hypertonicity, acid treatment, or K+ depletion inhibited internalization of NHE3.
Moreover, transient transfection of an inhibitory mutant of dynamin
(DynS45N) blocked the clathrin-mediated uptake of transferrin, as well
as the endocytosis of NHE3. In ileal villus cells, endogenous NHE3 was
also found to co-purify with isolated clathrin-coated vesicles, thereby
confirming their association in native tissues. The role of COP-I
subunits in the intracellular traffic of NHE3 was evaluated using
ldlF cells, which bear a temperature-sensitive mutation in
the
The Epithelial Na+/H+ Exchanger, NHE3, Is
Internalized through a Clathrin-mediated Pathway*
§,
,§§
Division of Respiratory Medicine, Department
of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada,
the ¶ Division of Gastroenterology, The Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205, the
§ Division of Cell Biology, Research Institute, The Hospital
for Sick Children, Toronto, Ontario M5G 1X8, Canada, and the
Department of Physiology, McGill
University, Montréal, Québec, H3G 1Y6, Canada
-COP subunit. At the permissive temperature, NHE3 distributed
normally, whereas at the restrictive temperature, which induces rapid
degradation of -COP, NHE3 was still internalized, but its
subcellular distribution was altered. These results indicate that
endocytosis of NHE3 occurs primarily via clathrin-coated pits and
vesicles and that normal intracellular trafficking of NHE3 involves an
-COP-dependent step.
*
This work was supported by the Medical Research Council of
Canada 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.
Industry Research Scholar. Supported by the American Digestive
Health Foundation of the United States.
**
International Scholar of the Howard Hughes Medical Institute and is
the current holder of the Pitbaldo Chair in Cell Biology at the
Hospital for Sick Children. Cross-appointed to the Department of
Biochemistry, University of Toronto.
§§
Medical Research Council of Canada Scientist. To whom
correspondence should be addressed: Dept. of Physiology, McGill
University, McIntyre Medical Science Bldg., 3655 Drummond St.,
Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-8335; Fax:
514-398-7452; E-mail: orlowski@med.mcgill.ca.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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