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| Subject Categories: Membranes & Transport | Molecular Biology of Disease |
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| The EMBO Journal
(2006) 25, 5049–5057, doi:10.1038/sj.emboj.7601387 Published online 19 October 2006 |
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| Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3- secretion: relevance to cystic fibrosis |
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| Youxue Wang1, Abigail A Soyombo1, Nikolay Shcheynikov1, Weizhong Zeng1, Michael Dorwart1, Christopher R Marino2, Philip J Thomas1 and Shmuel Muallem1 |
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1 The Department of Physiology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA 2 Department of Medicine, University of Tennessee, Memphis, TN, USA To whom correspondence should be addressed Shmuel Muallem, The Department of Physiology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9040, USA. Tel.: +1 214 645 6008; Fax: +1 214 645 6089; E-mail: Shmuel.Muallem@UTSouthwestern.edu Received 15 May 2006; Accepted 18 September 2006; Published online 19 October 2006. |
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| Abstract |
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| Fluid and HCO3- secretion are vital functions of the pancreatic duct and other secretory epithelia. CFTR and Cl-/HCO3- exchange activity at the luminal membrane are required for these functions. The molecular identity of the Cl-/HCO3- 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 CFTRinh-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. |
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| Keywords: CFTR, fluid and HCO3 - secretion, pancreatic duct, slc26a6 |
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