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Am J Physiol Gastrointest Liver Physiol (November 6, 2003). doi:10.1152/ajpgi.00355.2003
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Submitted on August 18, 2003
Accepted on October 29, 2003

Vesicular exocytosis contributes to volume-sensitive ATP release in biliary cells

David Gatof1*, Gordan Kilic1, and J. Gregory Fitz1

1 Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: david.gatof{at}uchsc.edu.

Extracellular ATP is a potent autocrine/paracrine signal that regulates a broad range of liver functions through activation of purinergic receptors. In biliary epithelium, increases in cell volume stimulate ATP release through a phosphoinositide 3-kinase (PI 3-kinase) dependent mechanism. Since PI 3-kinase also regulates vesicular exocytosis, the purpose of these studies was to determine whether volume-stimulated vesicular exocytosis contributes to cellular ATP release. In a human cholangiocarcinoma cell line, exocytosis was measured using the plasma membrane marker FM1-43, while ATP release was assessed using a luciferase-luciferin assay. Under basal conditions cholangiocytes exhibited constitutive exocytosis at a rate of 1.6 % min-1, and low levels of extracellular ATP were detected at 48.2 arbitrary light units (ALU). Increases in cholangiocyte cell volume induced by hypotonic exposure resulted in a 10-fold increase in the rate of exocytosis, and a robust 35-fold increase in ATP release. Both vesicular exocytosis and ATP release were proportional to cell volume, and both exhibited similar regulatory properties including: 1) dependence on intact PI 3-kinase, 2) attenuation by inhibition of protein kinase C (PKC) and 3) potentiation by activation of protein kinase C prior to hypotonic exposure. These findings demonstrate that increases in cholangiocyte cell volume stimulate ATP release and vesicular exocytosis through similar regulatory paradigms. Functional interactions between cell volume, PKC, and PI 3-kinase modulate exocytosis thereby regulating ATP release and purinergic signaling in cholangiocytes. It is hypothesized that protein kinase C is involved in the recruitment of a volume-sensitive vesicular pool to a readily releasable state.




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