Bile secretion is one of the principal functions of the liver. In order to maintain bile flow, not only must hepatocytes secrete bile, but this must then be modified and conditioned further by bile duct epithelial cells, or cholangiocytes. Abnormal cholangiocytes function results in cholestasis, which is a cardinal manifestation of liver disease. Cholestatic liver diseases are responsible for 20% of liver transplants in the US, and are the most common cause of liver disease among pediatric transplant patients. In addition, abnormal cholangiocyte function is responsible for the hepatic manifestations of cystic fibrosis, one of the most common inherited diseases. Bile secretion in cholangiocytes is regulated in part by cytosolic Ca2+. In general, cells are regulated both by the pattern of Ca2+ signals over time and by the regions of the cells in which Ca2+ signals occur. However, little is known about temporal or spatial aspects of Ca2+ signaling in cholangiocytes, and nothing is known about how these Ca2+ signals are regulated. Inositol 1,4,5-trisphosphate receptors (InsP3R) mediate Ca2+ signaling in epithelia, and cholangiocytes express all three isoforms of this receptor. The hypothesis of this proposal is that Ca2+ signals in the cholangiocyte are regulated by the subcellular distribution of the InsP3R isoforms. This hypothesis will be investigated through the following specific aims: The function and regulation of the InsP3Rs will be compared at the single channel level. The contribution that each of the receptors plays to Ca2+ signaling in cholangiocytes will be examined in a bile duct cell line modified to express either one or a combination of these receptors. These findings will be related to the organization of Ca2+ signals and secretory function in native cholangiocytes, as determined in isolated microperfused bile duct segments. This work should not only identify the molecular mechanisms responsible for Ca2+ signaling in cholangiocytes, but serve as a model for how the molecular organization of signaling pathways is responsible for regulation of ductular secretion.
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