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 journalArticle

115 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 Jan 1

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Bicarbonates
Permeability
Phosphotransferases
Pancreatic Ducts
Proline
Alanine
Oxidative Stress
Pancreatic Juice
Guinea Pigs
Digestive System Physiological Phenomena
Cystic Fibrosis
Lysine
Pancreas

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Park, Hyun Woo ; Nam, Joo Hyun ; Kim, Joo Young ; Namkung, Wan ; Yoon, Jae Seok ; Lee, Jung Soo ; Kim, Kyung Sik ; Venglovecz, Viktoria ; Gray, Michael A. ; Kim, Kyung Hwan ; Lee, Min Goo. / Dynamic regulation of CFTR bicarbonate permeability by [Cl -]i and its role in pancreatic bicarbonate secretion. In: Gastroenterology. 2010 ; Vol. 139, No. 2. pp. 620-631.
@article{801f3510df6349a7a5e67fb24d96774a,
title = "Dynamic regulation of CFTR bicarbonate permeability by [Cl -]i and its role in pancreatic bicarbonate secretion",
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.",
author = "Park, {Hyun Woo} and Nam, {Joo Hyun} and Kim, {Joo Young} and Wan Namkung and Yoon, {Jae Seok} and Lee, {Jung Soo} and Kim, {Kyung Sik} and Viktoria Venglovecz and Gray, {Michael A.} and Kim, {Kyung Hwan} and Lee, {Min Goo}",
year = "2010",
month = "1",
day = "1",
doi = "10.1053/j.gastro.2010.04.004",
language = "English",
volume = "139",
pages = "620--631",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "2",

}

Park, HW, Nam, JH, Kim, JY, Namkung, W, Yoon, JS, Lee, JS, Kim, KS, Venglovecz, V, Gray, MA, Kim, KH & Lee, MG 2010, 'Dynamic regulation of CFTR bicarbonate permeability by [Cl -]i and its role in pancreatic bicarbonate secretion', Gastroenterology, vol. 139, no. 2, pp. 620-631. https://doi.org/10.1053/j.gastro.2010.04.004

Dynamic regulation of CFTR bicarbonate permeability by [Cl -]i and its role in pancreatic bicarbonate secretion. / Park, Hyun Woo; Nam, Joo Hyun; Kim, Joo Young; Namkung, Wan; Yoon, Jae Seok; Lee, Jung Soo; Kim, Kyung Sik; Venglovecz, Viktoria; Gray, Michael A.; Kim, Kyung Hwan; Lee, Min Goo.

In: Gastroenterology, Vol. 139, No. 2, 01.01.2010, p. 620-631.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dynamic regulation of CFTR bicarbonate permeability by [Cl -]i and its role in pancreatic bicarbonate secretion

AU - Park, Hyun Woo

AU - Nam, Joo Hyun

AU - Kim, Joo Young

AU - Namkung, Wan

AU - Yoon, Jae Seok

AU - Lee, Jung Soo

AU - Kim, Kyung Sik

AU - Venglovecz, Viktoria

AU - Gray, Michael A.

AU - Kim, Kyung Hwan

AU - Lee, Min Goo

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77955480968&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955480968&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2010.04.004

DO - 10.1053/j.gastro.2010.04.004

M3 - Article

VL - 139

SP - 620

EP - 631

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -