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

Viktória Venglovecz, Péter Hegyi, Zoltán Rakonczay, László Tiszlavicz, Antonio Nardi, Morten Grunnet, Michael A. Gray

Research output: Contribution to journalArticle

30 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 1 2011

ASJC Scopus subject areas

  • Gastroenterology

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