Protective Role Of Calcium Signalling Regulators In Pancreatic Acinar Cells

Acute pancreatitis is a life threatening illness characterized by premature activation of digestiveenzymes inside pancreatic acinar cells. This leads to necrosis and digestion of the pancreatictissue and its surroundings. As of yet, no specific therapy to treat acute pancreatitis has beenfound.The physiological and pathological processes are controlled to a large extent by calciumsignalling in pancreatic acinar cells. Intracellular calcium signalling not only regulates theexpression and secretion of digestive enzymes but also contributes to the activation oftrypsinogen, which eventually leads to pancreatitis and causes necrosis of pancreatic tissue.The Bcl-2protein is a member of Bcl-2family proteins that regulate programmed cell death. Ithas been shown that Bcl-2proteins are engaged in the regulation of cellular calcium homeostasis.One aim of this study was to investigate the effects of the anti-apoptotic Bcl-2protein onintracellular calcium fluxes. Another goal was to study the effects of calmodulin activators(calcium-like peptides) on pathophysiological processes in pancreatic acinar cells.Our data showed that thapsigargin-induced cytosolic calcium clearance was quicker in pancreaticacinar cells lacking Bcl-2protein than in wild type cells. We blocked the endoplasmic reticulumCa2+pumps by thapsigargin and removed the external Ca2+, therefore, Ca2+extrusion was theonly process restoring the basal cytosolic Ca2+level. Our results show that cells lacking Bcl-2extrudes Ca2+more efficiently than the wild type cells. Furthermore, Ca2+extrusion wasdecreased in the pancreatic cancer cell line AR42J which has overexpression of Bcl-2. This effectcan be explained by the increased activity of plasma membrane calcium-activated ATPase(PMCA) which was blocked by Caloxin3A1, which in turn promotes necrosis in pancreaticacinar cells.In addition, the data presented here showed that the calmodulin activators CALP-3and CALP-1 did not affect the physiological calcium signalling in pancreatic acinar cells but insteadcontributed to either increasing the cell survival rate or causing apoptosis. CALPs were appliedto specifically activate calmodulin which reduced the toxic effects of pancreatic acinar cellschallenged with alcohol or the oxidant menadione.This study shows that the inhibition of calcium recovery mechanisms by Bcl-2is significantlypathological whilst restricting calcium release by CALPs is beneficial and protective. The studyalso proposes that calcium-like peptides could potentially be developed as therapeutic agents foracute pancreatitis.