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

Hyun Woo Park, Joo Hyun Nam, Joo Young Kim, Wan Namkung, Jae Seok Yoon, Jung Soo Lee, Kyung Sik Kim, Viktoria Venglovecz, Michael A. Gray, Kyung Hwan Kim, Min Goo Lee

Research output: Contribution to journalArticlepeer-review

149 Citations (Scopus)


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 HCO 3 - 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 HCO 3 - 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 HCO 3 --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.

Original languageEnglish
Pages (from-to)620-631
Number of pages12
Issue number2
Publication statusPublished - 2010

Bibliographical note

Funding Information:
Funding Supported by grants 2010-0001670 from the National Research Foundation of Korea , Ministry of Education, Science and Technology, Korea, and A030001 from the Korea Health 21 R&D Project , Ministry of Health & Welfare, Korea.

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology


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