Large cholangiocytes, from large ducts, express secretin receptors on the basolateral membrane and express cystic fibrosis transmembrane conductance regulator (CFTR) and the HCO3−/Cl− anion exchanger 2 (AE2) on the apical membrane,2-4 and hence respond to secretin with an increase in [cAMP] (intracellular cyclic adenosine monophosphate concentration), and subsequent Cl− and HCO3− efflux into the lumen. Conversely, small cholangiocytes, selleck inhibitor from small ducts, do not express secretin receptors, CFTR, or HCO3−/Cl− exchanger and do not exhibit a secretory response

to secretin.3 In human liver, parallel to the findings observed in the rat and mouse, secretin-stimulated duct secretory activity is heterogeneous, because only medium and large interlobular bile ducts express the Cl−/HCO3− exchanger AE2.5 Recently, secretion mediated by extracellular nucleotides (e.g., adenosine triphosphate [ATP]) acting on purinergic (P2) receptors on the luminal membrane of biliary epithelial cells has emerged as functionally important. ATP is present in bile,6 and binding of ATP to P2 receptors increases K+7,8 and Cl− efflux from isolated cholangiocytes9, this website 10 and dramatically increases transepithelial secretion

in biliary epithelial monolayers.10, 11 Indeed, the magnitude of the secretory response to ATP is two-fold to three-fold greater than that to cAMP.10 Interestingly, recent evidence suggests that even cAMP-stimulated bile flow is mediated by ATP release into the duct lumen and stimulation of apical P2 receptors.12 Together, these studies challenge

and extend the conventional model that centers on the concept that cAMP-dependent opening of CFTR-related Cl− channels is the driving force for cholangiocyte secretion. MCE Rather, the operative regulatory pathways appear to take place within the lumen of intrahepatic ducts, where release of ATP into bile is a final common pathway controlling ductular bile formation. In light of recent studies demonstrating that the mechanical effects of fluid-flow or shear stress at the apical membrane of biliary epithelial cells is a robust stimulus for ATP release,13 a model emerges in which mechanosensitive ATP release and Cl− secretion is a dominant pathway regulating biliary secretion. Although cholangiocytes express a repertoire of both P2X and P2Y receptors,11, 14, 15 it is unknown if expression differs between small and large cholangiocytes and/or if functional differences exist in ATP release and signaling along the bile duct. The aim of the current studies therefore was to determine if a potential P2 signaling axis may exist along the bile duct by evaluating mechanosensitive ATP release and exocytosis, P2 receptor expression and function, and secretion mediated by extracellular nucleotides in both small (MSC) and large (MLC) mouse cholangiocytes.