Pathophysiological relevance of apical large-conductance Ca 2+-activated potassium channels in pancreatic duct epithelial cells

V. Venglovecz, P. Hegyi, Z. Rakonczay, L. Tiszlavicz, Antonio Nardi, Morten Grunnet, Michael A. Gray

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background: Acute pancreatitis is among the few inflammatory diseases for which no specific pharmacological treatment is available. It has previously been shown that bile acids alter pancreatic ductal secretion and these effects are probably involved in the pathogenesis of bile-induced pancreatitis. Objective: To understand the mechanism responsible for bile-induced hypersecretion and, in particular, to identify the molecular target for bile acids in native pancreatic duct epithelial cells (PDECs). Methods: Patch clamp recordings and spectrofluorimetry were used to measure whole cell currents and rates of HCO3- secretion, respectively, from isolated guinea pig pancreatic ducts. Expression of ion channels and receptors was investigated by immunohistochemistry/immunofluorescence of intact pancreatic tissue. Results: Exposing PDECs to chenodeoxycholate (CDC, 100 μM) reversibly increased whole cell K+ currents and hyperpolarised cell membrane potential. Bile acid-stimulated K+ currents were inhibited by Ba2+ (2 mM), iberiotoxin (100 nM), and suppressed by strong intracellular Ca2+ buffering. Luminally applied iberiotoxin also blocked CDC-stimulated HCO 3- secretion from microperfused ducts; however, the inhibitor did not influence the stimulatory effect of secretin, carbachol or luminally applied ATP. The specific large-conductance Ca2+-activated potassium (BK) channel activator, NS11021, induced a similar increase in HCO3- secretion to CDC. Immunohistochemical analysis showed strong BK channel protein expression on the apical membrane of PDECs, while the G-protein-coupled bile acid receptor-1 was not detected in PDECs, but was present in acinar cells. Conclusion: It was shown for the first time that BK channels (i) are expressed at the apical membrane of guinea pig PDECs; (ii) have a crucial role in regulating HCO3- secretion and (iii) are also essential for the bile acid-induced hypersecretion and, therefore, underlie the response of the pancreas to this noxious agent.

Original languageEnglish
Pages (from-to)361-369
Number of pages9
JournalGut
Volume60
Issue number3
DOIs
Publication statusPublished - Mar 2011

Fingerprint

Pancreatic Ducts
Potassium Channels
Bile Acids and Salts
Epithelial Cells
Large-Conductance Calcium-Activated Potassium Channels
Centers for Disease Control and Prevention (U.S.)
Bile
Pancreatitis
Guinea Pigs
Chenodeoxycholic Acid
Secretin
Membranes
Acinar Cells
Carbachol
Ion Channels
GTP-Binding Proteins
Membrane Potentials
Fluorescent Antibody Technique
Pancreas
Adenosine Triphosphate

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Pathophysiological relevance of apical large-conductance Ca 2+-activated potassium channels in pancreatic duct epithelial cells. / Venglovecz, V.; Hegyi, P.; Rakonczay, Z.; Tiszlavicz, L.; Nardi, Antonio; Grunnet, Morten; Gray, Michael A.

In: Gut, Vol. 60, No. 3, 03.2011, p. 361-369.

Research output: Contribution to journalArticle

@article{a64531719ad14a119d2f4eb91d537b05,
title = "Pathophysiological relevance of apical large-conductance Ca 2+-activated potassium channels in pancreatic duct epithelial cells",
abstract = "Background: Acute pancreatitis is among the few inflammatory diseases for which no specific pharmacological treatment is available. It has previously been shown that bile acids alter pancreatic ductal secretion and these effects are probably involved in the pathogenesis of bile-induced pancreatitis. Objective: To understand the mechanism responsible for bile-induced hypersecretion and, in particular, to identify the molecular target for bile acids in native pancreatic duct epithelial cells (PDECs). Methods: Patch clamp recordings and spectrofluorimetry were used to measure whole cell currents and rates of HCO3- secretion, respectively, from isolated guinea pig pancreatic ducts. Expression of ion channels and receptors was investigated by immunohistochemistry/immunofluorescence of intact pancreatic tissue. Results: Exposing PDECs to chenodeoxycholate (CDC, 100 μM) reversibly increased whole cell K+ currents and hyperpolarised cell membrane potential. Bile acid-stimulated K+ currents were inhibited by Ba2+ (2 mM), iberiotoxin (100 nM), and suppressed by strong intracellular Ca2+ buffering. Luminally applied iberiotoxin also blocked CDC-stimulated HCO 3- secretion from microperfused ducts; however, the inhibitor did not influence the stimulatory effect of secretin, carbachol or luminally applied ATP. The specific large-conductance Ca2+-activated potassium (BK) channel activator, NS11021, induced a similar increase in HCO3- secretion to CDC. Immunohistochemical analysis showed strong BK channel protein expression on the apical membrane of PDECs, while the G-protein-coupled bile acid receptor-1 was not detected in PDECs, but was present in acinar cells. Conclusion: It was shown for the first time that BK channels (i) are expressed at the apical membrane of guinea pig PDECs; (ii) have a crucial role in regulating HCO3- secretion and (iii) are also essential for the bile acid-induced hypersecretion and, therefore, underlie the response of the pancreas to this noxious agent.",
author = "V. Venglovecz and P. Hegyi and Z. Rakonczay and L. Tiszlavicz and Antonio Nardi and Morten Grunnet and Gray, {Michael A.}",
year = "2011",
month = "3",
doi = "10.1136/gut.2010.214213",
language = "English",
volume = "60",
pages = "361--369",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "3",

}

TY - JOUR

T1 - Pathophysiological relevance of apical large-conductance Ca 2+-activated potassium channels in pancreatic duct epithelial cells

AU - Venglovecz, V.

AU - Hegyi, P.

AU - Rakonczay, Z.

AU - Tiszlavicz, L.

AU - Nardi, Antonio

AU - Grunnet, Morten

AU - Gray, Michael A.

PY - 2011/3

Y1 - 2011/3

N2 - Background: Acute pancreatitis is among the few inflammatory diseases for which no specific pharmacological treatment is available. It has previously been shown that bile acids alter pancreatic ductal secretion and these effects are probably involved in the pathogenesis of bile-induced pancreatitis. Objective: To understand the mechanism responsible for bile-induced hypersecretion and, in particular, to identify the molecular target for bile acids in native pancreatic duct epithelial cells (PDECs). Methods: Patch clamp recordings and spectrofluorimetry were used to measure whole cell currents and rates of HCO3- secretion, respectively, from isolated guinea pig pancreatic ducts. Expression of ion channels and receptors was investigated by immunohistochemistry/immunofluorescence of intact pancreatic tissue. Results: Exposing PDECs to chenodeoxycholate (CDC, 100 μM) reversibly increased whole cell K+ currents and hyperpolarised cell membrane potential. Bile acid-stimulated K+ currents were inhibited by Ba2+ (2 mM), iberiotoxin (100 nM), and suppressed by strong intracellular Ca2+ buffering. Luminally applied iberiotoxin also blocked CDC-stimulated HCO 3- secretion from microperfused ducts; however, the inhibitor did not influence the stimulatory effect of secretin, carbachol or luminally applied ATP. The specific large-conductance Ca2+-activated potassium (BK) channel activator, NS11021, induced a similar increase in HCO3- secretion to CDC. Immunohistochemical analysis showed strong BK channel protein expression on the apical membrane of PDECs, while the G-protein-coupled bile acid receptor-1 was not detected in PDECs, but was present in acinar cells. Conclusion: It was shown for the first time that BK channels (i) are expressed at the apical membrane of guinea pig PDECs; (ii) have a crucial role in regulating HCO3- secretion and (iii) are also essential for the bile acid-induced hypersecretion and, therefore, underlie the response of the pancreas to this noxious agent.

AB - Background: Acute pancreatitis is among the few inflammatory diseases for which no specific pharmacological treatment is available. It has previously been shown that bile acids alter pancreatic ductal secretion and these effects are probably involved in the pathogenesis of bile-induced pancreatitis. Objective: To understand the mechanism responsible for bile-induced hypersecretion and, in particular, to identify the molecular target for bile acids in native pancreatic duct epithelial cells (PDECs). Methods: Patch clamp recordings and spectrofluorimetry were used to measure whole cell currents and rates of HCO3- secretion, respectively, from isolated guinea pig pancreatic ducts. Expression of ion channels and receptors was investigated by immunohistochemistry/immunofluorescence of intact pancreatic tissue. Results: Exposing PDECs to chenodeoxycholate (CDC, 100 μM) reversibly increased whole cell K+ currents and hyperpolarised cell membrane potential. Bile acid-stimulated K+ currents were inhibited by Ba2+ (2 mM), iberiotoxin (100 nM), and suppressed by strong intracellular Ca2+ buffering. Luminally applied iberiotoxin also blocked CDC-stimulated HCO 3- secretion from microperfused ducts; however, the inhibitor did not influence the stimulatory effect of secretin, carbachol or luminally applied ATP. The specific large-conductance Ca2+-activated potassium (BK) channel activator, NS11021, induced a similar increase in HCO3- secretion to CDC. Immunohistochemical analysis showed strong BK channel protein expression on the apical membrane of PDECs, while the G-protein-coupled bile acid receptor-1 was not detected in PDECs, but was present in acinar cells. Conclusion: It was shown for the first time that BK channels (i) are expressed at the apical membrane of guinea pig PDECs; (ii) have a crucial role in regulating HCO3- secretion and (iii) are also essential for the bile acid-induced hypersecretion and, therefore, underlie the response of the pancreas to this noxious agent.

UR - http://www.scopus.com/inward/record.url?scp=79851510346&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79851510346&partnerID=8YFLogxK

U2 - 10.1136/gut.2010.214213

DO - 10.1136/gut.2010.214213

M3 - Article

C2 - 20940280

AN - SCOPUS:79851510346

VL - 60

SP - 361

EP - 369

JO - Gut

JF - Gut

SN - 0017-5749

IS - 3

ER -