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

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122 Citations (Scopus)

Abstract

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
JournalGastroenterology
Volume139
Issue number2
DOIs
Publication statusPublished - 2010

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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    Park, H. W., Nam, J. H., Kim, J. Y., Namkung, W., Yoon, J. S., Lee, J. S., Kim, K. S., Venglovecz, V., Gray, M. A., Kim, K. H., & Lee, M. G. (2010). Dynamic regulation of CFTR bicarbonate permeability by [Cl -]i and its role in pancreatic bicarbonate secretion. Gastroenterology, 139(2), 620-631. https://doi.org/10.1053/j.gastro.2010.04.004