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J. Biol. Chem., Vol. 269, Issue 38, 23544-23552, 09, 1994
A Kapus, S Grinstein, S Wasan, R Kandasamy and J Orlowski
Four distinct isoforms of the mammalian Na+/H+ exchanger (NHE) have been
identified by molecular cloning. Three of these (NHE-1, NHE-2, and NHE-3)
have been shown to be functionally active by heterologous expression. Their
kinetic and pharmacological properties are well documented, yet
comparatively little is known about their regulation. In this report, rat
NHE-1, NHE-2, and NHE-3 were stably transfected into antiporter-deficient
Chinese hamster ovary cells to study their role in cellular proliferation
and their regulation by nucleotides and cell volume. Their ability to
influence cell proliferation was assessed by measuring the growth of
antiporter-deficient cells and of the different transfectants in media of
varying pH. While antiporter- deficient cells were unable to grow at acidic
pH levels, all three isoforms supported proliferation under these
conditions. Therefore, while the epithelia-specific isoforms (NHE-2 and
NHE-3) are thought to play primarily a role in transcellular ion transport,
they can also contribute to intracellular pH (pHi) homeostasis and have a
permissive role in cell growth. The activity of the three isoforms was
markedly inhibited by depletion of cellular ATP. In the pHi 6.0-7.2 range,
decreases in the affinity for internal H+ and/or the maximal rate of
transport accounted for the inhibitory effect, depending on the isoform.
The osmotic responsiveness of the three isoforms was also compared. As
reported earlier, NHE-1 was stimulated by hypertonicity. Under similar
conditions, NHE-2 was also stimulated to a comparable extent. Conversely,
both isoforms were inhibited in hypotonic media. In contrast, NHE-3 was
markedly inhibited by hypertonic cell shrinking but was unaffected by
hypotonicity. Osmotic inhibition of NHE-3 was rapid, reversible, and
apparent throughout the pH range studied. Osmotic inhibition of NHE-3 may
play a role in the physiology and pathophysiology of epithelia.
Functional characterization of three isoforms of the Na+/H+ exchanger stably expressed in Chinese hamster ovary cells. ATP dependence, osmotic sensitivity, and role in cell proliferation
Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
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H. Amlal, A. Goel, and M. Soleimani Activation of H+-ATPase by hypotonicity: a novel regulatory mechanism for H+ secretion in IMCD cells Am J Physiol Renal Physiol, October 1, 1998; 275(4): F487 - F501. [Abstract] [Full Text] [PDF]
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D. Eladari, A. Blanchard, F. Leviel, M. Paillard, A. K. Stuart-Tilley, S. L. Alper, and R.-A. Podevin Functional and molecular characterization of luminal and basolateral Cl-/HCO-3 exchangers of rat thick limbs Am J Physiol Renal Physiol, September 1, 1998; 275(3): F334 - F342. [Abstract] [Full Text] [PDF]
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D. W. Good Nerve growth factor regulates HCO-3 absorption in thick ascending limb: modifying effects of vasopressin Am J Physiol Cell Physiol, April 1, 1998; 274(4): C931 - C939. [Abstract] [Full Text] [PDF]
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F. LANG, G. L. BUSCH, M. RITTER, H. VOLKL, S. WALDEGGER, E. GULBINS, and D. HAUSSINGER Functional Significance of Cell Volume Regulatory Mechanisms Physiol Rev, January 1, 1998; 78(1): 247 - 306. [Abstract] [Full Text] [PDF]
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