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(Received for publication, April 16, 1997)
From the Division of Cell Biology, Research Institute, the Hospital
for Sick Children, Toronto M5G 1X8, Canada
The ubiquitous isoform of the
Na+/H+ exchanger (NHE1) is essential for
the regulation of cellular volume. The underlying molecular mechanism,
which is poorly understood, was studied in human polymorphonuclear leukocytes (PMN). Suspension of PMN in hypertonic media induced rapid
cellular shrinkage and activation of NHE1, which is measurable as a
cytosolic alkalinization. Concomitantly, hypertonic stress also induced
extensive tyrosine phosphorylation of several proteins. Pretreatment of PMN with genistein, a tyrosine kinase inhibitor, prevented not only the tyrosine phosphorylation in response to a
hypertonic shock but also the activation of NHE1. The signal elicited
by hyperosmolarity that induces activation of tyrosine kinases and NHE1
was investigated. Methods were devised to change medium osmolarity
without altering cell volume and vice versa. Increasing medium and
intracellular osmolarity in normovolemic cells failed to activate
tyrosine kinases or NHE1. However, shrinkage of cells under iso-osmotic
conditions stimulated both tyrosine phosphorylation and NHE1 activity.
These findings imply that cells detect alterations in cell size but not
changes in osmolarity or ionic strength. The identity of the proteins
that were tyrosine-phosphorylated in response to cell shrinkage was
also investigated. Unexpectedly, the mitogen-activated protein kinases
SAPK, p38, erk1, and erk2 were not detectably
phosphorylated or activated. In contrast, the tyrosine kinases
p59fgr and p56/59hck were phosphorylated and activated
upon hypertonic challenge. We propose that cells respond to alterations
in cell size, but not to changes in osmolarity, with increased tyrosine
phosphorylation, which in turn leads to the activation of NHE1. The
resulting changes in ion content and cytosolic pH contribute to the
restoration of cell volume in shrunken cells.
Volume 272, Number 28,
Issue of July 11, 1997
pp. 17303-17311
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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