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, Yulong Zhang, William R. Skach, William B. Guggino, J. Kevin Foskett, John F. Engelhardt

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)645-657
Number of pages13
JournalJournal of Cell Biology
Volume143
Issue number3
DOIs
StatePublished - Nov 2 1998

Keywords

  • ATP release
  • CFTR
  • Cl sensor
  • Oocytes

ASJC Scopus subject areas

  • Cell Biology

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    Jiang, Q., Mak, D., Devidas, S., Schwiebert, E. M., Bragin, A., Zhang, Y., Skach, W. R., Guggino, W. B., Foskett, J. K., & Engelhardt, J. F. (1998). Cystic fibrosis transmembrane conductance regulator-associated atp release is controlled by a chloride sensor. Journal of Cell Biology, 143(3), 645-657. https://doi.org/10.1083/jcb.143.3.645