CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR-ASSOCIATED ATP RELEASE IS CONTROLLED BY A CHLORIDE SENSOR

Citation
Qs. Jiang et al., CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR-ASSOCIATED ATP RELEASE IS CONTROLLED BY A CHLORIDE SENSOR, The Journal of cell biology, 143(3), 1998, pp. 645-657
Citations number
52
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell Biology
Journal title
ISSN journal
0021-9525
Volume
143
Issue
3
Year of publication
1998
Pages
645 - 657
Database
ISI
SICI code
0021-9525(1998)143:3<645:CTCRAR>2.0.ZU;2-H
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a ch loride channel that is defective in cystic fibrosis, and has also been closely associated with ATP permeability in cells. Using a Xenopus oo cyte cRNA expression system, we have evaluated the molecular mechanism s that control CFTR-modulated ATP release. CFTR-modulated ATP release was dependent on both cAMP activation and a gradient change in the ext racellular chloride concentration. Activation of ATP release occurred within a narrow concentration range of external Cl- that was similar t o that reported in airway surface fluid. Mutagenesis of CFTR demonstra ted that Cl- conductance and ATP release regulatory properties could b e dissociated to different regions of the CFTR protein. Despite the la ck 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 (wtCF TR, Cl >> Br; R347P, Cl >> Br; R347E, Br >> Cl; R334W, Cl = Br). We hy pothesize that residues R347 and R334 may contribute a Cl- binding sit e within the CFTR channel pore that is necessary for activation of ATP efflux in response to increases of extracellular Cl-. In summary, the se findings suggest a novel chloride sensor mechanism by which CFTR is capable of responding to changes in the extracellular chloride concen tration by modulating the activity of an unidentified ATP efflux pathw ay. This pathway may play an important role in maintaining fluid and e lectrolyte balance in the airway through purinergic regulation of epit helial cells. Insight into these molecular mechanisms enhances our und erstanding of pathogenesis in the cystic fibrosis lung.