Phosphatase inhibitors activate normal and defective CFTR chloride channels

Frédéric Becq, Timothy J. Jensen, Xiu Bao Chang, Anna Savoia, Johanna M. Rommens, Lap Chee Tsui, Manuel Buchwald, John R. Riordan, John W. Hanrahan

Research output: Contribution to journalArticlepeer-review

140 Scopus citations


The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is regulated by phosphorylation and dephosphorylation at multiple sites. Although activation by protein kinases has been studied in some detail, the dephosphorylation step has received little attention. This report examines the mechanisms responsible for the dephosphorylation and spontaneous deactivation ('rundown') of CFTR chloride channels excised from transfected Chinese hamster ovary (CHO) and human airway epithelial cells. We report that the alkaline phosphate inhibitors bromotetramisole, 3-isobutyl-1- methylxanthine, theophylline, and vanadate slow the rundown of CFTR channel activity in excised membrane patches and reduce dephosphorylation of CFTR protein in isolated membranes. It was also found that in unstimulated cells, CFTR channels can be activated by exposure to phosphatase inhibitors alone. Most importantly, exposure of mammalian cells to phosphatase inhibitors alone activates CFTR channels that have disease-causing mutations, provided the mutant channels are present in the plasma membrane (R117H, G551D, and ΔF508 after cooling). These results suggest that CFTR dephosphorylation is dynamic and that membrane-associated phosphatase activity may be a potential therapeutic target for the treatment of cystic fibrosis.

Original languageEnglish (US)
Pages (from-to)9160-9164
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
StatePublished - Sep 13 1994


  • cystic fibrosis transmembrane conductance regulator
  • rundown

ASJC Scopus subject areas

  • General


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