Mechanisms of intracellular zymogen activation.
The pancreatic acinar cell is potentially the initial site of injury that begins the series of events leading to acute pancreatitis. Pathological intrapancreatic zymogen activation occurs in experimental pancreatitis in animals and in human pancreatitis. Intracellular activation has been clearly linked to aberrant zymogen processing in one form of hereditary pancreatitis; in this genetic disease a mutation in cationic trypsinogen may eliminate the degradation of any trypsin activated in the acinar cell. Recent studies have also provided the first direct evidence that trypsinogen activation takes place early in the course of caerulein-induced pancreatitis; parallel studies have used isolated pancreatic acini and conditions that simulate those that cause pancreatitis in vivo to demonstrate that zymogens can be pathologically activated in isolated cells. A unique acinar cell pathway regulates the intracellular proteinase processing of zymogens to their active forms. Stimulating the acinar cell with supramaximal concentrations of cholecystokinin (CCK) or carbamylcholine can activate this pathway. The activation depends on a low pH compartment within the acinar cell and activation of an intracellular serine protease. A marker of trypsinogen processing, the trypsinogen activation peptide (TAP), is generated in acinar cell compartments that do not overlap with secretory granules. This compartment overlaps with a marker of recycling endosomes and lysosomes. Thus, zymogen processing within the acinar cell proceeds in a distinct subcellular compartment and is dependent on a low pH environment and activation of serine proteases.
Gorelick
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Department of Medicine and Cell Biology, VA Connecticut Healthcare System, Yale University School of Medicine, West Haven 06516, USA.
Otani
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D000208:Acute Disease; D000818:Animals; D002766:Cholecystokinin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009842:Oligopeptides / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology*; D010195:Pancreatitis / Q000201:enzymology* / Q000503:physiopathology; D012680:Sensitivity and Specificity; D012697:Serine Endopeptidases / Q000097:blood
D004792:Enzyme Precursors; D009842:Oligopeptides; C080396:trypsinogen activation peptide; D000431:Ethanol; D002766:Cholecystokinin; D012697:Serine Endopeptidases