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Inhibitors of Bcl-2 protein family deplete ER Ca2+ stores in pancreatic acinar cells

Gerasimenko, Julia Vladimirovna, Ferdek, Pawel, Fischer, Lars, Gukovskaya, Anna and Pandol, Stephen 2010. Inhibitors of Bcl-2 protein family deplete ER Ca2+ stores in pancreatic acinar cells. Pflugers Archiv-European Journal of Physiology 460 (5) , pp. 891-900. 10.1007/s00424-010-0859-4

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Abstract

Physiological stimulation of pancreatic acinar cells by cholecystokinin and acetylcholine activate a spatial-temporal pattern of cytosolic [Ca+2] 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+2] 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+2] and endoplasmic reticulum [Ca+2]. 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 [Ca2+] 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+2] changes are regulated by differential cellular distribution of interacting pairs of prosurvival and proapoptotic Bcl-2 proteins.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Q Science > QP Physiology
Uncontrolled Keywords: pancreas; pancreatic acinar cell; acetylcholine; transport; signal transduction; cell death
Publisher: Springer
ISSN: 0031-6768
Last Modified: 12 Jun 2019 02:41
URI: http://orca-mwe.cf.ac.uk/id/eprint/18655

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