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J Physiol Volume 586, Number 11, 2779-2798, June 1, 2008 DOI: 10.1113/jphysiol.2008.153015
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ALIMENTARY

Fluid flow induces mechanosensitive ATP release, calcium signalling and Cl– transport in biliary epithelial cells through a PKC{zeta}-dependent pathway

 Kangmee Woo1, Amal K. Dutta1, Vishal Patel2, Charles Kresge1 and Andrew P. Feranchak1

1 Department of Pediatrics
2 Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9063, USA

ATP in bile is a potent secretogogue, stimulating cholangiocyte Cl– and fluid secretion via binding to membrane P2 receptors, though the physiological stimuli involved in biliary ATP release are unknown. The goal of the present studies was to determine the potential role of fluid flow in biliary ATP release and secretion. In both human Mz-Cha-1 biliary cells and normal rat cholangiocyte monolayers, exposure to flow increased relative ATP release which was proportional to the shear stress. In parallel studies, shear was associated with an increase in [Ca2+]i and membrane Cl– permeability, which were both dependent on extracellular ATP and P2 receptor stimulation. Flow-stimulated ATP release was dependent on [Ca2+]i, exhibited desensitization with repetitive stimulation, and was regulated by PKC{zeta}. In conclusion, both human and rat biliary cells exhibit flow-stimulated, PKC{zeta}-dependent, ATP release, increases in [Ca2+]i and Cl– secretion. The finding that fluid flow can regulate membrane transport suggests that mechanosensitive ATP release may be a key regulator of biliary secretion and an important target to modulate bile flow in the treatment of cholestatic liver diseases.

(Received 25 February 2008; accepted after revision 31 March 2008; first published online 3 April 2008)
Corresponding author A. Feranchak: UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9063, USA. Email: drew.feranchak{at}utsouthwestern.edu

This paper has online supplemental material.


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