NDLI: Inhibitors of Bcl-2 protein family deplete ER $Ca^{2+}$ stores in pancreatic acinar cells

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Gerasimenko, Julia Ferdek, Pawel Fischer, Lars Gukovskaya, Anna S. Pandol, Stephen J.
Description	Country affiliation: United kingdom Author Affiliation: Gerasimenko J ( The Physiological Laboratory, University of Liverpool, Liverpool, L69 3BX, UK.)
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 (IP(3)Rs), 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 IP(3)Rs and RyRs and substantially reduced by strong [Ca(2+)] buffering. Inhibition of IP(3)Rs 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.
File Format	HTM / HTML
ISSN	00316768
e-ISSN	14322013
DOI	10.1007/s00424-010-0859-4
Journal	Pflügers Archiv - European Journal of Physiology
Issue Number	5
Volume Number	460
Language	English
Publisher	Springer
Publisher Date	2010-10-01
Publisher Place	Germany
Access Restriction	Open
Subject Keyword	Discipline Physiology Calcium Metabolism Pancreas, Exocrine Proto-oncogene Proteins C-bcl-2 Antagonists & Inhibitors Animals Apoptosis Drug Effects Benzamides Pharmacology Benzopyrans Cell Line, Tumor Endoplasmic Reticulum Inositol 1,4,5-trisphosphate Receptors Physiology Mice Nitriles Cytology Ryanodine Receptor Calcium Release Channel Bcl-2-associated X Protein Bcl-x Protein Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Research Support, U.s. Gov't, Non-p.h.s.
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Clinical Biochemistry

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