Intracellular activation of digestive zymogens in rat pancreatic acini stimulation by high doses of cholecystokinin

Steven D. Leach, Irvin M. Modlin, George A. Scheele, Fred S. Gorelick

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanism by which digestive zymogens become activated during acute pancreatitis remains poorly understood. Given the ability for cholecystokinin (CCK) to induce pancreatitis in vivo, the effects of high dose CCK on preparations of isolated pancreatic acini were examined. Using an immunologic technique for the detection of zymogen activation, CCK was found to stimulate the conversion of procarboxypeptidase A1 to a 35-kD form having the same net charge and electrophoretic mobility as purified recombinant carboxypeptidase A1. This enhanced conversion was proportional to the dose of CCK (maximal at 100 nM), and time dependent. CCK also produced changes in the electrophoretic mobility of procarboxypeptidase B and chymotrypsinogen 2 immunoreactivity, consistent with activation of these zymogens. These events were detectable only within acinar cell pellets and not in the incubation medium, suggesting an intracellular site of conversion. The conversion of procarboxypeptidase A1 to its active form was inhibited by pretreatment with the weak base chloroquine (40 μM) and the protonophore monensin (10 μM). This conversion was also inhibited by pretreatment with the serine protease inhibitor benzamidine (10 mM) but not the cysteine protease inhibitor E64 (100 μM). The results suggest that high dose CCK stimulates the intracellular activation of digestive zymogens within isolated pancreatic acini. This event appears to require an acidic subcellular compartment and serine protease activity.

Original languageEnglish (US)
Pages (from-to)362-366
Number of pages5
JournalJournal of Clinical Investigation
Volume87
Issue number1
DOIs
StatePublished - Jan 1991

Keywords

  • Acinar cell
  • Cholecystokinin
  • Pancreas
  • Pancreatitis
  • Proteases

ASJC Scopus subject areas

  • Medicine(all)

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