Excessive ethanol (EtOH) consumption and biliary tract diseases are the most common etiological factors of acute pancreatitis. In vivo pancreatitis animal models have revealed that not only acinar cells, but most probably the pancreatic ductal epithelial cells (PDEC) are also involved in the pathogenesis of acute pancreatitis (ref.1). One of the main aims of our workgroup is to understand the role of PDEC in acute pancreatitis. In recent years we have characterized the effects of different bile acids, ethanol, ethanol-metabolites and activated proteases on PDEC function. Both EtOH and bile acids have dual effects on pancreatic ductal bicarbonate secretion. Low concentrations of these toxic factors stimulate, whereas high concentrations, inhibit the secretory process. Importantly, the stimulatory effects of both toxic factors are calcium dependent. EtOH and bile acids induce an oscillatory calcium elevation which can be blocked by BAPTA-AM, caffeine, xestospongin C and the phospholipase C inhibitor U73122, but not by the lack of extracellular calcium (ref.2). Administration of high concentrations of EtOH, bile acids and fatty acids induce a sustained calcium elevation. This sustained calcium elevation is caused by (1) calcium release from the endoplasmic reticulum, via IP3 and ryanodine receptor activation;(2) by inhibiting the endoplasmic reticulum calcium ATPase and (3) by stimulating extracellular calcium influx. Blocking this sustained calcium elevation by BAPTA-AM prevents the inhibitory effects of EtOH and fatty acids, but not that caused by bile acids. The inactive protease trypsinogen has no effect on calcium, however, trypsin induces calcium elevation via activation of PAR2. Inhibiting this calcium elevation, either by trypsin inhibitor, a PAR antagonist or BAPTA-AM totally blocks the inhibitory effect of trypsin (ref.3). These results indicate that pancreatitis-inducing factors strongly and differentially modulate intracellular calcium, which interferes with the secretory activity of PDEC. Understanding the calcium transporters/channels involved in these pathophysiological mechanisms may lead to more specific therapies for acute pancreatitis.