Calcium-dependent regulation of secretion in biliary epithelial cells: The role of apamin-sensitive SK channels

Andrew P. Feranchak, R. Brian Doctor, Marlyn Troetsch, Kathryn Brookman, Sylene M. Johnson, J. Gregory Fitz

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Background & Aims: Increases in intracellular Ca2+ are thought to complement cAMP in stimulating Cl- secretion in cholangiocytes, although the site(s) of action and channels involved are unknown. We have identified a Ca2+-activated K+ channel (SK2) in biliary epithelium that is inhibited by apamin. The purpose of the present studies was to define the role of SK channels in Ca2+- dependent cholangiocyte secretion. Methods: Studies were performed in human Mz-Cha-1 cells and normal rat cholangiocytes (NRC). Currents were measured by whole-cell patch clamp technique and transepithelial secretion by Ussing chamber. Results: Ca2+-dependent stimuli, including purinergic receptor stimulation, ionomycin, and increases in cell volume, each activated K+-selective currents with a linear IV relation and time-dependent inactivation. Currents were Ca2+ dependent and were inhibited by apamin and by Ba2+. In intact liver, immunoflourescence with an antibody to SK2 showed a prominent signal in cholangiocyte plasma membrane. To evaluate the functional significance, NRC monolayers were mounted in a Ussing chamber, and the short-circuit current (Isc) was measured. Exposure to ionomycin caused an increase in Isc 2-fold greater than that induced by cAMP. Both the basal and ionomycin-induced Isc were inhibited by basolateral Ba2+, and ∼58% of the basolateral K + current was apamin sensitive. Conclusions: These studies demonstrate that cholangiocytes exhibit robust Ca2+-stimulated secretion significantly greater in magnitude than that stimulated by cAMP. SK2 plays an important role in mediating the increase in transepithelial secretion due to increases in intracellular Ca2+. SK2 channels, therefore, may represent a target for pharmacologic modulation of bile flow.

Original languageEnglish (US)
Pages (from-to)903-913
Number of pages11
JournalGastroenterology
Volume127
Issue number3
DOIs
StatePublished - Sep 2004

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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