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J. Biol. Chem., Vol. 279, Issue 4, 2962-2974, January 23, 2004

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Acute Regulation of Na/H Exchanger NHE3 by Adenosine A₁ Receptors Is Mediated by Calcineurin Homologous Protein^*

Francesca Di Sole¶, Robert Cerull, Victor Babich, Henry Quiñones, Serge M. Gisler||, Jürg Biber||, Heini Murer||, Gerhard Burckhardt, Corinna Helmle-Kolb**, and Orson W. Moe**

From the ;Department of Internal Medicine and ;Center of Mineral Metabolism and Clinical Research, Medical Center, University of Texas Southwestern, Dallas, Texas 75390-8856, the Medical Service, Veterans Affairs Medical Center, Dallas, Texas 75216, the Department of Physiology and Pathophysiology, Georg-August-University of Göttingen, Göttingen 37073, Germany, and the ^||Institute of Physiology, University of Zürich, Zürich 8057, Switzerland

Adenosine is an autacoid that regulates renal Na⁺ transport. Activation of adenosine A₁ receptor (A₁R) by N⁶-cyclopentidyladenosine (CPA) inhibits the Na⁺/H⁺ exchanger 3 (NHE3) via phospholipase C/Ca²⁺/protein kinase C (PKC) signaling pathway. Mutation of PKC phosphorylation sites on NHE3 does not affected regulation of NHE3 by CPA, but amino acid residues 462 and 552 are essential for A₁R-dependent control of NHE3 activity. One binding partner of the NHE family is calcineurin homologous protein (CHP). We tested the role of NHE3-CHP interaction in mediating CPA-induced inhibition of NHE3 in opossum kidney (OK) and Xenopus laevis uroepithelial (A6) cells. Both native and transfected NHE3 and CHP are present in the same immuno-complex by co-immunoprecipitation. CPA (10^-6 M) increases CHP-NHE3 interaction by 30 - 60% (native and transfected proteins). Direct CHP-NHE3 interaction is evident by yeast two-hybrid assay (bait, NHE3_{C terminus}; prey, CHP); the minimal interacting region is localized to the juxtamembrane region of NHE3_{C terminus} (amino acids 462-552 of opossum NHE3). The yeast data were confirmed in OK cells where truncated NHE3 (NHE3⁵⁵²) still shows CPA-stimulated CHP interaction. Overexpression of the polypeptide from the CHP binding region (NHE3^462-552) interferes with the ability of CPA to inhibit NHE3 activity and to increase CHPNHE3_Full-length interaction. Reduction of native CHP expression by small interference RNA abolishes the ability of CPA to inhibit NHE3 activity. We conclude that CHPNHE3 interaction is regulated by A₁R activation and this interaction is a necessary and integral part of the signaling pathway between adenosine and NHE3.

Received for publication, June 26, 2003 , and in revised form, October 6, 2003.

^* This work was supported in part by the National Institutes of Health Grants R01-DK-48482 and R01-DK-54392 (to O. W. M.), by American Heart Association Texas Affiliate Grant 98G-052 (to O. W. M.), by the Department of Veteran Affairs Research Service (to O. W. M.), by National Institutes of Health National Research Service Award T32 DK07257-2031 (to H. Q.), by the Deutsche Forschungsgemeinschaft (Grant HE 2416/2-1 to C. H.-K.), and by the Swiss National Science Foundation (Grants 31-46523.96 and 31-65397.01 to H. M.). 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.

^** Both authors contributed equally to the work.

^¶ Recipient of American Heart Association Texas award (0325098Y). To whom correspondence should be addressed: Dept. of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8856. Tel.: 214-648-3152; Fax: 214-648-2071; e-mail: Francesca.DiSole{at}UTsouthwestern.edu.

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