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Regulation of Ca 2+ signaling in rat bile duct epithelia by inositol 1,4,5‐trisphosphate receptor isoforms
Author(s) -
Hirata Keiji,
Dufour JeanFrançois,
Shibao Kazunori,
Knickelbein Roy,
O'Neill Allison F.,
Bode HansPeter,
Cassio Doris,
StPierre Marie V.,
LaRusso Nicholas F.,
Leite M. Fatima,
Nathanson Michael H.
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.34432
Subject(s) - cholangiocyte , ryanodine receptor , microbiology and biotechnology , inositol , subcellular localization , biology , gene isoform , cytosol , second messenger system , inositol trisphosphate receptor , signal transduction , receptor , medicine , chemistry , biochemistry , endocrinology , endoplasmic reticulum , cytoplasm , enzyme , gene
Cytosolic Ca 2+ (Ca i 2+ ) regulates secretion of bicarbonate and other ions in the cholangiocyte. In other cell types, this second messenger acts through Ca 2+ waves, Ca 2+ oscillations, and other subcellular Ca 2+ signaling patterns, but little is known about the subcellular organization of Ca 2+ signaling in cholangiocytes. Therefore, we examined Ca 2+ signaling and the subcellular distribution of Ca 2+ release channels in cholangiocytes and in a model cholangiocyte cell line. The expression and subcellular distribution of inositol 1,4,5‐trisphosphate (InsP 3 ) receptor (InsP 3 R) isoforms and the ryanodine receptor (RyR) were determined in cholangiocytes from normal rat liver and in the normal rat cholangiocyte (NRC) polarized bile duct cell line. Subcellular Ca 2+ signaling in cholangiocytes was examined by confocal microscopy. All 3 InsP 3 R isoforms were expressed in cholangiocytes, whereas RyR was not expressed. The type III InsP 3 R was the most heavily expressed isoform at the protein level and was concentrated apically, whereas the type I and type II isoforms were expressed more uniformly. The type III InsP 3 R was expressed even more heavily in NRC cells but was concentrated apically in these cells as well. Adenosine triphosphate (ATP), which increases Ca 2+ via InsP 3 in cholangiocytes, induced Ca 2+ oscillations in both cholangiocytes and NRC cells. Acetylcholine (ACh) induced apical‐to‐basal Ca 2+ waves. In conclusion, Ca 2+ signaling in cholangiocytes occurs as polarized Ca 2+ waves that begin in the region of the type III InsP 3 R. Differential subcellular localization of InsP 3 R isoforms may be an important molecular mechanism for the formation of Ca 2+ waves and oscillations in cholangiocytes. Because Ca i 2+ is in part responsible for regulating ductular secretion, these findings also may have implications for the molecular basis of cholestatic disorders.