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HORMONES AND SIGNALING

Zymogen activation in a reconstituted pancreatic acinar cell system

¹Department of Internal Medicine, Section of Digestive Diseases, and the ²Department of Cell Biology, Veterans Administration Connecticut Healthcare, West Haven, and Yale University School of Medicine, New Haven, Connecticut

Submitted 18 November 2005 ; accepted in final form 28 November 2005

Pathological activation of digestive zymogens within the pancreatic acinar cell initiates acute pancreatitis. Cytosolic events regulate this activation within intracellular compartments of unclear identity. In an in vivo model of acute pancreatitis, zymogen activation was detected in both zymogen granule-enriched and microsomal cellular fractions. To examine the mechanism of this activation in vitro, a reconstituted system was developed using pancreatic cytosol, a zymogen granule-enriched fraction, and a microsomal fraction. Addition of cytosol to either particulate fraction resulted in a prominent increase in both trypsin and chymotrypsin activities. The percentage of the pool of trypsinogen and chymotrypsinogen activated was about twofold and sixfold greater, respectively, in the microsomal than in the zymogen granule-enriched fraction. Activation of chymotrypsinogen but not trypsinogen was significantly enhanced by ATP (5 mM) but not by the inactive ATP analog AMP-PNP. The processing of procarboxypeptidase B to its mature form also demonstrated a requirement for ATP and cytosol. E64d, an inhibitor of cathepsin B, a thiol protease that can activate trypsin, completely inhibited trypsin activity but did not affect chymotrypsin activity or carboxypeptidase B generation. These studies demonstrate that both zymogen granule-enriched and microsomal fractions from the pancreas can support cytosol-dependent zymogen activation. A component of the activation of some zymogens, such as chymotrypsinogen and procarboxypeptidase, may depend on ATP but not on trypsin or cathepsin B.

trypsin(ogen); chymotrypsin(ogen); procarboxypeptidase B; cathepsin B; zymogen granule-enriched fraction; microsomal fraction

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				E. C. Thrower, S. Osgood, C. A. Shugrue, T. R. Kolodecik, A. M. Chaudhuri, J. R. Reeve Jr, S. J. Pandol, and F. S. Gorelick The novel protein kinase C isoforms -{delta} and -{varepsilon} modulate caerulein-induced zymogen activation in pancreatic acinar cells Am J Physiol Gastrointest Liver Physiol, June 1, 2008; 294(6): G1344 - G1353. [Abstract] [Full Text] [PDF]