Article

Fluid flow induces mechanosensitive ATP release, calcium signalling and Cl- transport in biliary epithelial cells through a PKCzeta-dependent pathway.

UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9063, USA.
The Journal of Physiology (impact factor: 4.72). 07/2008; 586(Pt 11):2779-98. DOI:10.1113/jphysiol.2008.153015
Source: PubMed

ABSTRACT 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 PKCzeta. In conclusion, both human and rat biliary cells exhibit flow-stimulated, PKCzeta-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.

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Keywords

ATP release
 
biliary ATP release
 
exhibited desensitization
 
extracellular ATP
 
Flow-stimulated ATP release
 
human Mz-Cha-1 biliary cells
 
increases
 
key regulator
 
mechanosensitive ATP release
 
membrane P2 receptors
 
membrane transport
 
modulate bile flow
 
P2 receptor stimulation
 
physiological stimuli
 
potent secretogogue
 
potential role
 
rat biliary cells exhibit flow-stimulated
 
relative ATP release
 
repetitive stimulation
 
shear stress