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Dynamic regulation of CFTR bicarbonate permeability by [Cl-]i and its role in pancreatic bicarbonate secretion.

 Boram Cha  ;  Joo Weon Lim  ;  Kyung Hwan Kim  ;  Hyeyong Kim 
 GASTROENTEROLOGY, Vol.139(2) : 620-631, 2010 
Journal Title
Issue Date
Animals ; Antiporters/genetics ; Antiporters/metabolism ; Bicarbonates/metabolism* ; Cell Line, Tumor ; Cell Membrane Permeability* ; Cell Polarity ; Chloride-Bicarbonate Antiporters ; Chlorides/metabolism* ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism* ; Guinea Pigs ; Humans ; Intracellular Signaling Peptides and Proteins ; Membrane Potentials ; Membrane Transport Proteins/metabolism ; Mice ; Minor Histocompatibility Antigens ; Pancreatic Juice/secretion ; Pancrelipase/metabolism* ; Pancrelipase/secretion ; Protein-Serine-Threonine Kinases/metabolism ; Time Factors ; Transfection ; WNK Lysine-Deficient Protein Kinase 1
CFTR ; Bicarbonate ; Pancreatic Secretion ; WNK1/OSR1/SPAK Kinases
BACKGROUND & 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.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Sik(김경식) ORCID logo https://orcid.org/0000-0001-9498-284X
Kim, Kyung Hwan(김경환)
Kim, Joo Young(김주영) ORCID logo https://orcid.org/0000-0003-2623-1491
Nam, Joo Hyun(남주현)
Park, Hyun Woo(박현우)
Yoon, Jae Seok(윤재석)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Lee, Jung Soo(이정수)
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