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*Cystic Fibrosis
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© The Rockefeller University Press, 0021-9525/1998//645 $5.00
The Journal of Cell Biology, Volume 143, Number 3, , 1998 645-657

Regular Articles

Cystic Fibrosis Transmembrane Conductance Regulator–associated ATP Release Is Controlled by a Chloride Sensor



Qinshi Jiang*, Daniel Mak§, Sreenivas Devidas||, Erik M. Schwiebert, Alvina Bragin{ddagger}, Yulong Zhang*, William R. Skach{ddagger}, William B. Guggino||, J. Kevin Foskett§, and John F. Engelhardt§

* Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; {ddagger} Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104; § Institute for Human Gene Therapy and Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104; || Department of Physiology and Medicine Divisions of Pediatrics and Nephrology, and Center for Medical Genetics, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, Maryland 21205; and Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is defective in cystic fibrosis, and has also been closely associated with ATP permeability in cells. Using a Xenopus oocyte cRNA expression system, we have evaluated the molecular mechanisms that control CFTR-modulated ATP release. CFTR-modulated ATP release was dependent on both cAMP activation and a gradient change in the extracellular chloride concentration. Activation of ATP release occurred within a narrow concentration range of external Cl– that was similar to that reported in airway surface fluid. Mutagenesis of CFTR demonstrated that Cl– conductance and ATP release regulatory properties could be dissociated to different regions of the CFTR protein. Despite the lack of a need for Cl– conductance through CFTR to modulate ATP release, alterations in channel pore residues R347 and R334 caused changes in the relative ability of different halides to activate ATP efflux (wtCFTR, Cl >> Br; R347P, Cl >> Br; R347E, Br >> Cl; R334W, Cl = Br). We hypothesize that residues R347 and R334 may contribute a Cl– binding site within the CFTR channel pore that is necessary for activation of ATP efflux in response to increases of extracellular Cl–. In summary, these findings suggest a novel chloride sensor mechanism by which CFTR is capable of responding to changes in the extracellular chloride concentration by modulating the activity of an unidentified ATP efflux pathway. This pathway may play an important role in maintaining fluid and electrolyte balance in the airway through purinergic regulation of epithelial cells. Insight into these molecular mechanisms enhances our understanding of pathogenesis in the cystic fibrosis lung.

Key Words: CFTR • ATP release • Cl– sensor • oocytes

Abbreviations used in this paper: ABC, ATP-binding cassette; CF, cystic fibrosis; ORCC, outwardly rectifying Cl– channel; TEV, two-electrode voltage clamp; Vm, transmembrane potential; Wc, whole cell.

Address all correspondence to Dr. John F. Engelhardt, Ph.D., Associate Professor, University of Iowa, Department of Anatomy and Cell Biology, 1-111 BSB, 51 Newton Road, Iowa City, IA 52242-1109. Tel.: (319) 335-7753. Fax: (319) 335-6581. E-mail: john-engelhardt{at}uiowa.edu


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