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Originally published In Press as doi:10.1074/jbc.M201862200 on October 25, 2002

J. Biol. Chem., Vol. 277, Issue 52, 50503-50509, December 27, 2002
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The Cystic Fibrosis Transmembrane Conductance Regulator Interacts with and Regulates the Activity of the HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> Salvage Transporter Human Na+-HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> Cotransport Isoform 3*

Meeyoung ParkDagger §, Shigeru B. H. KoDagger , Joo Young ChoiDagger , Gaia MuallemDagger , Philip J. ThomasDagger , Alexander Pushkin, Myeong-Sok Lee||, Joo Young Kim**, Min Goo Lee**, Shmuel MuallemDagger Dagger Dagger , and Ira Kurtz

From the Dagger  Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, the  Department of Medicine, Division of Nephrology, UCLA, Los Angeles, California 90095, the || Department of Biological Sciences, Sookmyung Women's University, Seoul 140-742, Korea, and the ** Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea

Cystic fibrosis transmembrane conductance regulator (CFTR) regulates both HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> secretion and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> salvage in secretory epithelia. At least two luminal transporters mediate HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> salvage, the Na+/H+ exchanger (NHE3) and the Na+-HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> cotransport (NBC3). In a previous work, we show that CFTR interacts with NHE3 to regulate its activity (Ahn, W., Kim, K. W., Lee, J. A., Kim, J. Y., Choi, J. Y., Moe, O. M., Milgram, S. L., Muallem, S., and Lee, M. G. (2001) J. Biol. Chem. 276, 17236-17243). In this work, we report that transient or stable expression of human NBC3 (hNBC3) in HEK cells resulted in a Na+-dependent, DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid)- and 5-ethylisopropylamiloride-insensitive HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> transport. Stimulation of CFTR with forskolin markedly inhibited NBC3 activity. This inhibition was prevented by the inhibition of protein kinase A. NBC3 and CFTR could be reciprocally coimmunoprecipitated from transfected HEK cells and from the native pancreas and submandibular and parotid glands. Precipitation of NBC3 or CFTR from transfected HEK293 cells and from the pancreas and submandibular gland also coimmunoprecipitated EBP50. Glutathione S-transferase-EBP50 pulled down CFTR and hNBC3 from cell lysates when expressed individually and as a complex when expressed together. Notably, the deletion of the C-terminal PDZ binding motifs of CFTR or hNBC3 prevented coimmunoprecipitation of the proteins and inhibition of hNBC3 activity by CFTR. We conclude that CFTR and NBC3 reside in the same HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>-transporting complex with the aid of PDZ domain-containing scaffolds, and this interaction is essential for regulation of NBC3 activity by CFTR. Furthermore, these findings add additional evidence for the suggestion that CFTR regulates the overall trans-cellular HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> transport by regulating the activity of all luminal HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> secretion and salvage mechanisms of secretory epithelial cells.

* This work was supported by National Institutes of Health Grant DE12309, Grant MUALLE01G0 from the Cystic Fibrosis Foundation (to S. M.), and National Institutes of Health Grant DK58563 (to I. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Performed all of the experiments in this work as partial fulfillment of Ph.D. dissertation.

Dagger Dagger To whom correspondence should be addressed: University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9040. Tel.: 214-648-2593; Fax: 214-648-8879; E-mail: SHMUEL.MUALLEM@utsouthwestern.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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