A Novel Role for Bcl-2 in Regulation of Cellular Calcium Extrusion

• Published in: Current biology 2012-07, Vol.22 (13), p.1241-1246
• Main Authors: Ferdek, Pawel E., Gerasimenko, Julia V., Peng, Shuang, Tepikin, Alexei V., Petersen, Ole H., Gerasimenko, Oleg V.
• Format: Article
• Language: English
• Subjects: acinar cells; Acinar Cells - drug effects; Acinar Cells - metabolism; Animals; apoptosis; Apoptosis - genetics; Barium - metabolism; Ca(2+) Mg(2+)-ATPase - antagonists & inhibitors; calcium; Calcium - metabolism; Calcium Signaling; Cell Membrane - drug effects; Cell Membrane - metabolism; Cytosol - metabolism; endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; extrusion; gene overexpression; Inositol 1,4,5-Trisphosphate Receptors - metabolism; Meglumine; Mice; Mice, Inbred C57BL; Mice, Knockout; myo-inositol; necrosis; Necrosis - genetics; oxidative stress; Pancreas - cytology; Pancreas - pathology; Peptides - pharmacology; plasma membrane; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2; receptors; Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Vitamin K 3 - pharmacology
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2012.05.002

The antiapoptotic protein Bcl-2 [1, 2] plays important roles in Ca2+ signaling [3] by influencing inositol triphosphate receptors and regulating Ca2+-induced Ca2+ release [4–6]. Here we investigated whether Bcl-2 affects Ca2+ extrusion in pancreatic acinar cells. We specifically blocked the Ca2+ pumps in the endoplasmic reticulum and assessed the rate at which the cells reduced an elevated cytosolic Ca2+ concentration after a period of enhanced Ca2+ entry. Because external Ca2+ was removed and endoplasmic reticulum Ca2+ pumps were blocked, Ca2+ extrusion was the only process responsible for recovery. Cells lacking Bcl-2 restored the basal cytosolic Ca2+ level much faster than control cells. The enhanced Ca2+ extrusion in cells from Bcl-2 knockout (Bcl-2 KO) mice was not due to increased Na+/Ca2+ exchange activity, because removal of external Na+ did not influence the Ca2+ extrusion rate. Overexpression of Bcl-2 in the pancreatic acinar cell line AR42J decreased Ca2+ extrusion, whereas silencing Bcl-2 expression (siRNA) had the opposite effect. Loss of Bcl-2, while increasing Ca2+ extrusion, dramatically decreased necrosis and promoted apoptosis induced by oxidative stress, whereas specific inhibition of Ca2+ pumps in the plasma membrane (PMCA) with caloxin 3A1 reduced Ca2+ extrusion and increased necrosis. Bcl-2 regulates PMCA function in pancreatic acinar cells and thereby influences cell fate. ► Bcl-2 reduces Ca2+ extrusion through PMCA in control cells as compared to Bcl-2 KO ► Bcl-2 reduces Ca2+ extrusion though PMCA in AR42J cells overexpressing Bcl-2 ► Loss of Bcl-2 reduces Ca2+ overload, decreases necrosis, and promotes apoptosis