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J. Biol. Chem., Vol. 283, Issue 5, 2986-2996, February 1, 2008

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Role of NHERF1, Cystic Fibrosis Transmembrane Conductance Regulator, and cAMP in the Regulation of Aquaporin 9^*

Christine Pietrement, Nicolas Da Silva, Claudia Silberstein, Marianne James, Mireille Marsolais^¶, Alfred Van Hoek^||, Dennis Brown^||, Nuria Pastor-Soler^**, Nadia Ameen, Raynald Laprade^¶, Vijaya Ramesh^||, and Sylvie Breton^||1

From the Center for Systems Biology, Program in Membrane Biology/Nephrology Division and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, the ^||Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, the ^¶Groupe d'É_tude des Protéines Membranaires, Université de Montréal, Montréal, Canada, and the ^**Renal-Electrolyte Division and Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Water and solute transport across the plasma membrane of cells is a crucial biological function that is mediated mainly by aquaporins and aquaglyceroporins. The regulation of these membrane proteins is still incompletely understood. Using the male reproductive tract as a model system in which water and glycerol transport are critical for the establishment of fertility, we now report a novel pathway for the regulation of aquaporin 9 (AQP9) permeability. AQP9 is the major aquaglyceroporin of the epididymis, liver, and peripheral leukocytes, and its COOH-terminal portion contains a putative PDZ binding motif (SVIM). Here we show that NHERF1, cystic fibrosis transmembrane conductance regulator (CFTR), and AQP9 co-localize in the apical membrane of principal cells of the epididymis and the vas deferens, and that both NHERF1 and CFTR co-immunoprecipitate with AQP9. Overlay assays revealed that AQP9 binds to both the PDZ1 and PDZ2 domains of NHERF1, with an apparently higher affinity for PDZ1 versus PDZ2. Pull-down assays showed that the AQP9 COOH-terminal SVIM motif is essential for interaction with NHERF1. Functional assays on isolated tubules perfused in vitro showed a high permeability of the apical membrane to glycerol, which is inhibited by the AQP9 inhibitor, phloretin, and is markedly activated by cAMP. The CFTR inhibitors DPC, GlyH-101 and CFTRinh-172 all significantly reduced the cAMP-activated glycerol-induced cell swelling. We propose that CFTR is an important regulator of AQP9 and that the interaction between AQP9, NHERF1, and CFTR may facilitate the activation of AQP9 by cAMP.

Received for publication, June 6, 2007 , and in revised form, November 9, 2007.

^* This work was supported by National Institutes of Health Grant HD045821 (to S. B.), Cystic Fibrosis Foundation Grant BRETON05P0 (to S. B.), grants from the Committee of American Memorial Hospital of Reims, France, the Conseil Régional de Champagne-Ardenne, France, and the Ministère des Affaires Etrangères (Concours Lavoisier), France (to C. P.). The work performed in the Microscopy Core Facility of the Massachusetts General Hospital Program in Membrane Biology was supported by Center for the Study of Inflammatory Bowel Disease Grant DK43351 and Boston Area Diabetes and Endocrinology Research Center Award DK57521. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Program in Membrane Biology, Simches Research Center, Massachusetts General Hospital, 185 Cambridge St., Suite 8204, Boston, MA 02114. Tel.: 617-726-5785; Fax: 617-643-3182; E-mail: sbreton{at}partners.org.

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