Ca2+‐induced pancreatic cell death: Roles of the endoplasmic reticulum, zymogen granules, lysosomes and endosomes

Abstract Alcohol induces Ca 2+ ‐dependent intracellular trypsinogen activation in the apical granular area via non‐oxidative metabolites, such as fatty acid ethyl esters and fatty acids. Intracellular trypsinogen activation is a crucial initiating event in the development of acute pancreatitis, but the specific organelle in which this process takes place has been unknown. Recent data demonstrate that the Ca 2+ ‐dependent trypsinogen activation occurs in postexocytotic endocytic vacuoles. These vacuoles are acid due to a bafilomycin‐sensitive vacuolar H + ATPase and have a very Ca 2+ ‐permeable membrane. Acid endocytic structures, together with lysosomes, zymogen granules and elements of the endoplasmic reticulum, also play an important role in the physiological Ca 2+ signal generation that normally regulates enzyme and fluid secretion from the exocrine pancreas.