The role of Ca2+ influx in endocytic vacuole formation in pancreatic acinar cells.

Abstract

The inducers of acute pancreatitis trigger a prolonged increase in the cytosolic Ca(2+) concentration ([Ca(2+)]c), which is responsible for the damage to and eventual death of pancreatic acinar cells. Vacuolization is an important indicator of pancreatic acinar cell damage. Furthermore, activation of trypsinogen occurs in the endocytic vacuoles; therefore the vacuoles can be considered as 'initiating' organelles in the development of the cell injury. In the present study, we investigated the relationship between the formation of endocytic vacuoles and Ca(2+) influx developed in response to the inducers of acute pancreatitis [bile acid taurolithocholic acid 3-sulfate (TLC-S) and supramaximal concentration of cholecystokinin-8 (CCK)]. We found that the inhibitor of STIM (stromal interaction molecule)/Orai channels, GSK-7975A, effectively suppressed both the Ca(2+) influx (stimulated by inducers of pancreatitis) and the formation of endocytic vacuoles. Cell death induced by TLC-S or CCK was also inhibited by GSK-7975A. We documented the formation of endocytic vacuoles in response to store-operated Ca(2+) entry (SOCE) induced by thapsigargin [TG; inhibitor of sarcoplasmic/endoplasmic reticulum (ER) Ca(2+) pumps] and observed strong inhibition of TG-induced vacuole formation by GSK-7975A. Finally, we found that structurally-unrelated inhibitors of calpain suppress formation of endocytic vacuoles, suggesting that this Ca2+-dependent protease is a mediator between Ca(2+) elevation and endocytic vacuole formation.

• Authors: Svetlana Voronina, David Collier, Michael Chvanov, Ben Middlehurst, Alison J Beckett, Ian A Prior, David N Criddle, Malcolm Begg, Katsuhiko Mikoshiba, Robert Sutton, Alexei V Tepikin
• Journal: The Biochemical journal (Biochem J) Vol. 465 Issue 3 Pg. 405-12 (Feb 01 2015) ISSN: 1470-8728 [Electronic] England
• PMID: 25370603 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium

Topics

• Acinar Cells (metabolism)
• Animals
• Calcium (metabolism)
• Cells, Cultured
• Mice
• Pancreas (cytology, metabolism)
• Transport Vesicles (metabolism)
• Vacuoles (metabolism)