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Dynamic Regulation of CFTR Bicarbonate Permeability by [Cl^-]_i and Its Role in Pancreatic Bicarbonate Secretion

Lookup NU author(s): Viktoria Venglovecz, Dr Michael Gray

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Abstract

Bacground & Aims: Pancreatic bicarbonate (HCO3-) secretion is important for a healthy pancreas as well as digestive physiology. However, how human pancreatic duct cells secrete copious amounts of HCO3- has long been a puzzle. Here, we report that a dynamic increase in the cystic fibrosis transmembrane conductance regulator (CFTR) HCO3- permeability by intracellular Cl- concentration ([Cl-](i))-sensitive mechanisms plays a pivotal role in pancreatic HCO3- secretion. Methods: The role of [Cl-](i)-sensitive kinases in CFTR-mediated HCO3- transport was examined in heterologous expression systems, PANC1 human pancreatic duct cells, and human and guinea pig pancreatic tissues using an integrated molecular and physiologic approach. RESULTS: In human pancreatic tissues, CFTR-positive duct cells abundantly expressed with-no-lysine (WNK1) kinase, oxidative stress-responsive kinase 1 (OSR1), and sterile 20/SPS1-related proline/alanine-rich kinase (SPAK), which are known to be activated by low [Cl-](i). Interestingly, CFTR activation rapidly decreased [Cl-](i) in response to luminal Cl- depletion in polarized PANC1 human pancreatic duct cells. Notably, the WNK1-mediated OSR1 and SPAK activation by low [Cl-](i) strongly increased CFTR HCO3- permeability in CFTR-transfected HEK 293T, PANC1, and guinea pig pancreatic duct cells, making CFTR primarily an HCO3- channel, which is essential for the secretion of pancreatic juice containing HCO3- at a concentration greater than 140 mmol/L. In contrast, OSR1 and SPAK activation inhibited CFTR-dependent Cl-/HCO3- exchange activity that may reabsorb HCO3- from the high HCO3--containing pancreatic juice. Conclusions: These results indicate that the [Cl-](i)-sensitive activation of the WNK1-OSR1/SPAK pathway is the molecular switch to generate HCO3--rich fluid in the human pancreatic duct.

Publication metadata

Author(s): Park HW, Nam JH, Kim JY, Namkung W, Yoon JS, Lee JS, Kim KS, Venglovecz V, Gray MA, Kim KH, Lee MG

Publication type: Article

Publication status: Published

Journal: Gastroenterology

Year: 2010

Volume: 139

Issue: 2

Pages: 620-631

Print publication date: 14/04/2010

ISSN (print): 0016-5085

ISSN (electronic): 1528-0012

Publisher: WB Saunders Co.

URL: http://dx.doi.org/10.1053/j.gastro.2010.04.004

DOI: 10.1053/j.gastro.2010.04.004

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