Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells

Raraty, Michael, Ward, Jeremy, Erdemli, Gul, Vaillant, Camille, Neoptolemos, John P., Sutton, Robert and Petersen, Ole Holger ORCID: https://orcid.org/0000-0002-6998-0380 2000. Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells. Proceedings of the National Academy of Sciences of the United States of America 97 (24) , pp. 13126-13131. 10.1073/pnas.97.24.13126

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Abstract

The pancreatic acinar cell produces powerful digestive enzymes packaged in zymogen granules in the apical pole. Ca2+ signals elicited by acetylcholine or cholecystokinin (CCK) initiate enzyme secretion by exocytosis through the apical membrane. Intracellular enzyme activation is normally kept to a minimum, but in the often-fatal human disease acute pancreatitis, autodigestion occurs. How the enzymes become inappropriately activated is unknown. We monitored the cytosolic Ca2+ concentration ([Ca2+]i), intracellular trypsin activation, and its localization in isolated living cells with specific fluorescent probes and studied intracellular vacuole formation by electron microscopy as well as quantitative image analysis (light microscopy). A physiological CCK level (10 pM) eliciting regular Ca2+ spiking did not evoke intracellular trypsin activation or vacuole formation. However, stimulation with 10 nM CCK, evoking a sustained rise in [Ca2+]i, induced pronounced trypsin activation and extensive vacuole formation, both localized in the apical pole. Both processes were abolished by preventing abnormal [Ca2+]i elevation, either by preincubation with the specific Ca2+ chelator 1,2-bis(O-aminophenoxy)ethane-N,N-N′,N′-tetraacetic acid (BAPTA) or by removal of external Ca2+. CCK hyperstimulation evokes intracellular trypsin activation and vacuole formation in the apical granular pole. Both of these processes are mediated by an abnormal sustained rise in [Ca2+]i.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Systems Immunity Research Institute (SIURI)
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Last Modified:	27 Oct 2022 08:42
URI:	https://orca.cardiff.ac.uk/id/eprint/63169

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