Journal article
Cystic Fibrosis Transmembrane Conductance Regulator–associated ATP Release Is Controlled by a Chloride Sensor
The Journal of cell biology, Vol.143(3), pp.645-657
11/02/1998
DOI: 10.1083/jcb.143.3.645
PMCID: PMC2148142
PMID: 9813087
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.
Details
- Title: Subtitle
- Cystic Fibrosis Transmembrane Conductance Regulator–associated ATP Release Is Controlled by a Chloride Sensor
- Creators
- Qinshi Jiang - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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 MedicineDaniel Mak - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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 MedicineSreenivas Devidas - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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 MedicineErik M Schwiebert - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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 MedicineAlvina Bragin - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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 MedicineYulong Zhang - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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 MedicineWilliam R Skach - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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 MedicineWilliam B Guggino - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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 MedicineJ. Kevin Foskett - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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 MedicineJohn F Engelhardt - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109; 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
- Resource Type
- Journal article
- Publication Details
- The Journal of cell biology, Vol.143(3), pp.645-657
- DOI
- 10.1083/jcb.143.3.645
- PMID
- 9813087
- PMCID
- PMC2148142
- ISSN
- 0021-9525
- eISSN
- 1540-8140
- Language
- English
- Date published
- 11/02/1998
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984025579802771
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