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Vol. 12, Issue 12, 3717-3732, December 2001
and#
Na,K-ATPase is a key enzyme that regulates a variety of transport
functions in epithelial cells. In this study, we demonstrate a role for
Na,K-ATPase in the formation of tight junctions, desmosomes, and
epithelial polarity with the use of the calcium switch model in
Madin-Darby canine kidney cells. Inhibition of Na,K-ATPase either by ouabain or potassium depletion prevented the formation of
tight junctions and desmosomes and the cells remained nonpolarized. The
formation of bundled stress fibers that appeared transiently in control
cells was largely inhibited in ouabain-treated or potassium-depleted cells. Failure to form stress fibers correlated with a large reduction of RhoA GTPase activity in Na,K-ATPase-inhibited cells. In cells overexpressing wild-type RhoA GTPase, Na,K-ATPase inhibition did not
affect the formation of stress fibers, tight junctions, or desmosomes,
and epithelial polarity developed normally, suggesting that RhoA GTPase
is an essential component downstream of Na,K-ATPase-mediated regulation
of these junctions. The effects of Na,K-ATPase inhibition were mimicked
by treatment with the sodium ionophore gramicidin and were correlated
with the increased intracellular sodium levels. Furthermore, ouabain
treatment under sodium-free condition did not affect the formation of
junctions and epithelial polarity, suggesting that the intracellular
Na+ homeostasis plays a crucial role in generation of the
polarized phenotype of epithelial cells. These results thus demonstrate that the Na,K-ATPase activity plays an important role in regulating both the structure and function of polarized epithelial cells.
Department of Pathology and Laboratory Medicine,
University of California, Los Angeles, Los Angeles, California 90095;
*Department of Physiology, Weill Medical College of Cornell University,
New York, New York 10021; Department of Biochemistry,
University of Tennessee, Memphis, Tennessee 38163;
§Lankenau Medical Research Center, Wynnewood, Pennsylvania
19096; ¶Department of Cell Biology, The Scripps Research
Institute, La Jolla, California 92037; and Department of
Cell Biology and Physiology, University of Pittsburgh, Pittsburgh,
Pennsylvania 15261
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