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J Biol Chem, Vol. 274, Issue 6, 3414-3421, February 5, 1999

Regulation of Cl/ HCO₃ Exchange by Cystic Fibrosis Transmembrane Conductance Regulator Expressed in NIH 3T3 and HEK 293 Cells

Min Goo Lee, W. Christian Wigley, Weizhong Zeng, Laura E. Noel, Christopher R. Marino^¶, Philip J. Thomas, and Shmuel Muallem

From the  Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75235 and the ^¶ Department of Medicine and Physiology, University of Tennessee, Memphis, Tennessee 38163

A central function of cystic fibrosis transmembrane conductance regulator (CFTR)-expressing tissues is the secretion of fluid containing 100-140 mM HCO₃. High levels of HCO₃ maintain secreted proteins such as mucins (all tissues) and digestive enzymes (pancreas) in a soluble and/or inactive state. HCO₃ secretion is impaired in CF in all CFTR-expressing, HCO₃-secreting tissues examined. The mechanism responsible for this critical problem in CF is unknown. Since a major component of HCO₃ secretion in CFTR-expressing cells is mediated by the action of a Cl/HCO₃ exchanger (AE), in the present work we examined the regulation of AE activity by CFTR. In NIH 3T3 cells stably transfected with wild type CFTR and in HEK 293 cells expressing WT and several mutant CFTR, activation of CFTR by cAMP stimulated AE activity. Pharmacological and mutagenesis studies indicated that expression of CFTR in the plasma membrane, but not the Cl conductive function of CFTR was required for activation of AE. Furthermore, mutations in NBD2 altered regulation of AE activity by CFTR independent of their effect on Cl channel activity. At very high expression levels CFTR modified the sensitivity of AE to 4,4'-diisothiocyanatostilbene-2,2'-disulfonate. The novel finding of regulation of Cl/HCO₃ exchange by CFTR reported here may have important physiological implications and explain, at least in part, the impaired HCO₃ secretion in CF.

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