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The Calcineurin Homologous Protein-1 Increases Na⁺/H⁺-Exchanger 3 Trafficking via Ezrin Phosphorylation

Francesca Di Sole^*,,, Victor Babich^*, and Orson W. Moe^*,,

Departments of *Internal Medicine and
Physiology and
Charles and Jane Pak Center of Mineral Metabolism, University of Texas Southwestern Medical Center, Dallas, Texas; and
Institute for Cell and Molecular Biosciences, School of Biomedical Sciences, The Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom

Correspondence: Dr. Francesca Di Sole, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8885. Phone: 214-648-2850; Fax: 214-648-2526; E-mail: francesca.disole{at}utsouthwestern.edu

Received for publication December 11, 2008. Accepted for publication April 13, 2009.

The Na⁺/H⁺-exchanger 3 (NHE3) is essential for regulation of Na⁺ transport in the renal and intestinal epithelium. Although changes in cell surface abundance control NHE3 function, the molecular signals that regulate NHE3 surface expression are not well defined. We found that overexpression of the calcineurin homologous protein-1 (CHP1) in opossum kidney cells increased NHE3 transport activity, surface protein abundance, and ezrin phosphorylation. CHP1 knockdown by small interfering RNA had the opposite effects. Overexpression of wild-type ezrin increased both NHE3 transport activity and surface protein abundance, confirming that NHE3 is downstream of ezrin. Expression of a pseudophosphorylated ezrin enhanced these effects, whereas expression of an ezrin variant that could not be phosphorylated prevented the downstream effects on NHE3. Furthermore, CHP1 knockdown reversed the activation of NHE3 by wild-type ezrin but not by the pseudophosphorylated ezrin. Taken together, these results demonstrate that CHP1 increases NHE3 abundance and constitutive function in a manner dependent on ezrin phosphorylation.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673