Inhibitors of Bcl-2 protein family deplete ER Ca2 stores in pancreatic acinar cellsReport as inadecuate

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Pflügers Archiv - European Journal of Physiology

, Volume 460, Issue 5, pp 891–900

First Online: 09 July 2010Received: 12 January 2010Revised: 11 June 2010Accepted: 17 June 2010


Physiological stimulation of pancreatic acinar cells by cholecystokinin and acetylcholine activate a spatial-temporal pattern of cytosolic Ca changes that are regulated by a coordinated response of inositol 1,4,5-trisphosphate receptors IP3Rs, ryanodine receptors RyRs and calcium-induced calcium release CICR. For the present study, we designed experiments to determine the potential role of Bcl-2 proteins in these patterns of cytosolic Ca responses. We used small molecule inhibitors that disrupt the interactions between prosurvival Bcl-2 proteins i.e. Bcl-2 and Bcl-xl and proapoptotic Bcl-2 proteins i.e. Bax and fluorescence microfluorimetry techniques to measure both cytosolic Ca and endoplasmic reticulum Ca. We found that the inhibitors of Bcl-2 protein interactions caused a slow and complete release of intracellular agonist-sensitive stores of calcium. The release was attenuated by inhibitors of IP3Rs and RyRs and substantially reduced by strong Ca buffering. Inhibition of IP3Rs and RyRs also dramatically reduced activation of apoptosis by BH3I-2′. CICR induced by different doses of BH3I-2′ in Bcl-2 overexpressing cells was markedly decreased compared with control. The results suggest that Bcl-2 proteins regulate calcium release from the intracellular stores and suggest that the spatial-temporal patterns of agonist-stimulated cytosolic Ca changes are regulated by differential cellular distribution of interacting pairs of prosurvival and proapoptotic Bcl-2 proteins.

KeywordsPancreas Pancreatic acinar cell Acetylcholine Transport Signal transduction Cell death Julia Gerasimenko and Pawel Ferdek contributed equally to this work.

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Author: Julia Gerasimenko - Pawel Ferdek - Lars Fischer - Anna S. Gukovskaya - Stephen J. Pandol


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