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J. Cell Biol.,
Volume 143, Number 3, November 2, 1998 645-657




* Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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
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
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.
sensor;
oocytes
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