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Am J Physiol Gastrointest Liver Physiol 273: G1108-G1117, 1997;
0193-1857/97 $5.00
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Vol. 273, Issue 5, G1108-G1117, November 1997

Regulation of biliary secretion through apical purinergic receptors in cultured rat cholangiocytes

Thorsten Schlenker1, Joelle M.-J. Romac2, Ala I. Sharara2, Richard M. Roman1, Stephen J. Kim2, Nicholas Larusso3, Rodger A. Liddle2, and J. Gregory Fitz1

Departments of Medicine, 1 University of Colorado Health Sciences Center, Denver, Colorado 80262; 2 Duke University Medical Center, Durham, North Carolina 27710; and 3 Mayo Clinic, Rochester, Minnesota 55905

To evaluate whether ATP in bile serves as a signaling factor regulating ductular secretion, voltage-clamp studies were performed using a novel normal rat cholangiocyte (NRC) model. In the presence of amiloride (100 µM) to block Na+ channels, exposure of the apical membrane to ATP significantly increased the short-circuit current (Isc) from 18.2 ± 5.9 to 52.8 ± 12.7 µA (n = 18). The response to ATP is mediated by basolateral-to-apical Cl- transport because it is inhibited by 1) the Cl- channel blockers 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (1 mM), diphenylanthranilic acid (1.5 mM), or 5-nitro-2-(3-phenylpropylamino)benzoic acid (50 or 100 µM) in the apical chamber, 2) the K+ channel blocker Ba2+ (5 mM), or 3) the Na+-K+-2Cl- cotransport inhibitor bumetanide (200 µM) in the basolateral chamber. Other nucleotides stimulated an increase in Isc with a rank order potency of UTP = ATP = adenosine 5'-O-(3)-thiotriphosphate, consistent with P2u purinergic receptors. ADP, AMP, 2-methylthioadenosine 5'-triphosphate, and adenosine had no effect. A cDNA encoding a rat P2u receptor (rP2uR) was isolated from a liver cDNA library, and functional expression of the corresponding mRNA in Xenopus laevis oocytes resulted in the appearance of ATP-stimulated currents with a similar pharmacological profile. Northern analysis identified hybridizing mRNA transcripts in NRC as well as other cell types in rat liver. These findings indicate that exposure of polarized cholangiocytes to ATP results in luminal Cl- secretion through activation of P2u receptors in the apical membrane. Release of ATP into bile may serve as an autocrine or paracrine signal regulating cholangiocyte secretory function.

liver; chloride channel; ion transport; bile


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