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Originally published In Press as doi:10.1074/jbc.M011763200 on February 22, 2001

J. Biol. Chem., Vol. 276, Issue 20, 17236-17243, May 18, 2001
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Regulatory Interaction between the Cystic Fibrosis Transmembrane Conductance Regulator and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> Salvage Mechanisms in Model Systems and the Mouse Pancreatic Duct*

Wooin AhnDagger , Kyung Hwan KimDagger , Jin Ah LeeDagger , Joo Young KimDagger , Joo Young Choi§, Orson W. Moe, Sharon L. Milgram||, Shmuel Muallem§**, and Min Goo LeeDagger Dagger Dagger

From the Dagger  Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea, the Departments of § Physiology and  Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235, and the || Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599

The pancreatic duct expresses cystic fibrosis transmembrane conductance regulator (CFTR) and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> secretory and salvage mechanisms in the luminal membrane. Although CFTR plays a prominent role in HCO<UP><SUB><RM>3</RM></SUB><SUP><RM>−</RM></SUP></UP> secretion, the role of CFTR in HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> salvage is not known. In the present work, we used molecular, biochemical, and functional approaches to study the regulatory interaction between CFTR and the HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> salvage mechanism Na+/H+ exchanger isoform 3 (NHE3) in heterologous expression systems and in the native pancreatic duct. We found that CFTR regulates NHE3 activity by both acute and chronic mechanisms. In the pancreatic duct, CFTR increases expression of NHE3 in the luminal membrane. Thus, luminal expression of NHE3 was reduced by 53% in ducts of homozygote Delta F508 mice. Accordingly, luminal Na+-dependent and HOE694- sensitive recovery from an acid load was reduced by 60% in ducts of Delta F508 mice. CFTR and NHE3 were co-immunoprecipitated from PS120 cells expressing both proteins and the pancreatic duct of wild type mice but not from PS120 cells lacking CFTR or the pancreas of Delta F508 mice. The interaction between CFTR and NHE3 required the COOH-terminal PDZ binding motif of CFTR, and mutant CFTR proteins lacking the C terminus were not co-immunoprecipitated with NHE3. Furthermore, when expressed in PS120 cells, wild type CFTR, but not CFTR mutants lacking the C-terminal PDZ binding motif, augmented cAMP-dependent inhibition of NHE3 activity by 31%. These findings reveal that CFTR controls overall HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> homeostasis by regulating both pancreatic ductal HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> secretory and salvage mechanisms.

* This work was supported by Basic Research Program of the Korea Science and Engineering Foundation Grant 2000-2-21400-002-1 (to M. G. L.) and National Institutes of Health Grants DE12309 and DK38938 (to S. M.) and HL63755 (to S. L. M.).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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF307992 and AF307993.

** To whom correspondence may be addressed: Dept. of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9040. Tel.: 214 648 2593; Fax: 214 648 8879; E-mail: Shmuel.Muallem@UTSouthwestern.edu.

Dagger Dagger To whom correspondence may be addressed: Dept. of Pharmacology, Yonsei University College of Medicine, 134 Sinchon-Dong, Seoul 120-752, South Korea. Tel.: 82 2 361 5221; Fax: 82 2 313 1894; E-mail: mlee@yumc.yonsei.ac.kr.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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