Notably, overall rates of exocytosis in response to mechanosensitive stimuli did not vary significantly between MLCs and MSCs, despite a significantly check details greater release of ATP from MSCs, given the same stimulus. This may suggest the existence of distinct vesicle populations contributing to regulated ATP release. In fact, recent findings in rat liver cells suggest that a distinct population of ATP-enriched vesicles may contribute to regulated ATP release.27 In some cell types, the concentration of ATP within

secretory vesicles may approach 50 mM28 and, therefore, only several vesicles per cell may account for substantial differences in the concentration of ATP released into the extracellular space. Differences observed in the magnitude of ATP release between MSCs and MLCs may be related to variation in the regulation and/or trafficking

of specific vesicles involved in ATP transport (either ATP-containing vesicles and/or vesicles transporting an ATP transporter to the membrane). This regulation may occur at the level of vesicle “priming”, trafficking, or membrane fusion/release, though clearly further work is required. Nonetheless, if these observations apply to in vivo conditions, greater ATP release from small cholangiocytes would translate into a significant increase in the concentration of ATP in bile in the “upstream” intrahepatic ducts, given their smaller cross-sectional area and relative volume.29 Second, it is notable that extracellular nucleotides elicit secretory responses when applied at both apical and basolateral membranes. The apical membrane specifically represents Tanespimycin datasheet an anatomic orientation that is well suited for hepatocyte-to-cholangiocyte or cholangiocyte-to-cholangiocyte

signaling by release of ATP into bile. This is notably distinct from secretin and other hormones that are delivered to the basolateral membrane through the bloodstream.1 ATP release from the hepatocyte canalicular membrane may signal to downstream small and large cholangiocytes through apical P2 receptor stimulation in a process known as hepatobiliary coupling. Hepatobiliary coupling has also been described for bile acids, which are released from the hepatocyte canalicular membrane and may be transported into “downstream” cholangiocytes via the apical Na+-dependent bile acid transporter located on large, but not small, cholangiocytes.30 Interestingly, 上海皓元医药股份有限公司 Ursodeoxycholic acid is associated with cholangiocyte ATP release and Cl− secretion.24 Thus, the ductal concentration of ATP appears to be an important determinant of bile formation and may represent a final common pathway in coupling hepatocyte transport to cholangiocyte secretion. Lastly, the relative importance of secretin- versus P2 receptor-mediated secretion, in bile formation is unknown. The molecular identity of the Cl− channel(s) activated in response to ATP remains undefined in biliary epithelium, though it appears to be unrelated to CFTR.