The Journal of General Physiology
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Published online 12 April 2004 doi:10.1085/jgp.200308979
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 123, Number 5, 491-504
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Inhibition and Redistribution of NHE3, the Apical Na+/H+ Exchanger, by Clostridium difficile Toxin B

Hisayoshi Hayashi1, Katalin Szászi1, Natasha Coady-Osberg1, Wendy Furuya1, Anthony P. Bretscher2, John Orlowski3, and Sergio Grinstein1

1 Cell Biology Program, Hospital for Sick Children and Department of Biochemistry, University of Toronto, Ontario M5G 1X8, Canada
2 Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
3 Department of Physiology, McGill University, Montreal, Quebec, H3G 1Y6, Canada

Address correspondence to Sergio Grinstein, Hospital for Sick Children, Division of Cell Biology, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Fax: (416) 813-5028; email: sga{at}sickkids.on.ca

NHE3, the apical isoform of the Na+/H+ exchanger, is central to the absorption of salt and water across the intestinal epithelium. We report that treatment of epithelial cells with toxin B of Clostridium difficile, a diarrheal pathogen, causes a pronounced inhibition of NHE3 activity, with little effect on the basolateral NHE1 isoform. Depression of NHE3 activity is accompanied by the translocation of apical exchangers to a subapical endomembrane compartment. Treatment of cells with toxin B increased the fraction of exchangers that were solubilized by nonionic detergents and induced dephosphorylation and extensive redistribution of ezrin. The Rho-kinase inhibitor, Y-27632, also altered the distribution and activity of NHE3. We suggest that inactivation of Rho-family GTPases by clostridial toxin B alters the interaction between NHE3 and the microvillar cytoskeleton, possibly by impairing the ability of ezrin to bridge the exchangers to filamentous actin. Detachment of NHE3 from the actin skeleton would facilitate its internalization, resulting in net disappearance from the apical surface. The consequent inhibition of transport is likely to contribute to the diarrheal effects of C. difficile.

Key Words: Na/H exchange • antiport • pH regulation • Rho • ezrin

The online version of this article contains supplemental material.

Abbreviations used in this paper: HA, hemagglutinin; NHE, Na+/H+ exchanger.


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