Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3- secretion: Relevance to cystic fibrosis

Youxue Wang, Abigail A. Soyombo, Nikolay Shcheynikov, Weizhong Zeng, Michael Dorwart, Christopher R. Marino, Philip J. Thomas, Shmuel Muallem

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

Fluid and HCO3- secretion are vital functions of the pancreatic duct and other secretory epithelia. CFTR and Cl-/HCO 3- exchange activity at the luminal membrane are required for these functions. The molecular identity of the Cl-/HCO 3- exchangers and their relationship with CFTR in determining fluid and HCO3- secretion are not known. We show here that the Cl-/HCO3- exchanger slc26a6 controls CFTR activity and ductal fluid and HCO3- secretion. Unexpectedly, deletion of slc26a6 in mice and measurement of fluid and HCO3- secretion into sealed intralobular pancreatic ducts revealed that deletion of slc26a6 enhanced spontaneous and decreased stimulated secretion. Remarkably, inhibition of CFTR activity with CFTR inh-172, knock-down of CFTR by siRNA and measurement of CFTR current in WT and slc26a6-/- duct cells revealed that deletion of slc26a6 resulted in dis-regulation of CFTR activity by removal of tonic inhibition of CFTR by slc26a6. These findings reveal the intricate regulation of CFTR activity by slc26a6 in both the resting and stimulated states and the essential role of slc26a6 in pancreatic HCO3- secretion in vivo.

Original languageEnglish (US)
Pages (from-to)5049-5057
Number of pages9
JournalEMBO Journal
Volume25
Issue number21
DOIs
StatePublished - Nov 1 2006

Keywords

  • CFTR
  • Fluid and HCO secretion
  • Pancreatic duct
  • Slc26a6

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Wang, Y., Soyombo, A. A., Shcheynikov, N., Zeng, W., Dorwart, M., Marino, C. R., Thomas, P. J., & Muallem, S. (2006). Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3- secretion: Relevance to cystic fibrosis. EMBO Journal, 25(21), 5049-5057. https://doi.org/10.1038/sj.emboj.7601387