A novel role for Bcl-2 in regulation of cellular calcium extrusion.
The antiapoptotic protein Bcl-2 plays important roles in Ca(2+) signaling by influencing inositol triphosphate receptors and regulating Ca(2+)-induced Ca(2+) release. Here we investigated whether Bcl-2 affects Ca(2+) extrusion in pancreatic acinar cells. We specifically blocked the Ca(2+) pumps in the endoplasmic reticulum and assessed the rate at which the cells reduced an elevated cytosolic Ca(2+) concentration after a period of enhanced Ca(2+) entry. Because external Ca(2+) was removed and endoplasmic reticulum Ca(2+) pumps were blocked, Ca(2+) extrusion was the only process responsible for recovery. Cells lacking Bcl-2 restored the basal cytosolic Ca(2+) level much faster than control cells. The enhanced Ca(2+) extrusion in cells from Bcl-2 knockout (Bcl-2 KO) mice was not due to increased Na(+)/Ca(2+) exchange activity, because removal of external Na(+) did not influence the Ca(2+) extrusion rate. Overexpression of Bcl-2 in the pancreatic acinar cell line AR42J decreased Ca(2+) extrusion, whereas silencing Bcl-2 expression (siRNA) had the opposite effect. Loss of Bcl-2, while increasing Ca(2+) extrusion, dramatically decreased necrosis and promoted apoptosis induced by oxidative stress, whereas specific inhibition of Ca(2+) pumps in the plasma membrane (PMCA) with caloxin 3A1 reduced Ca(2+) extrusion and increased necrosis. Bcl-2 regulates PMCA function in pancreatic acinar cells and thereby influences cell fate.
Medical Research Council Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK.
Pawel E
PE
Ferdek
Julia V
JV
Gerasimenko
Shuang
S
Peng
Alexei V
AV
Tepikin
Ole H
OH
Petersen
Oleg V
OV
Gerasimenko
D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001464:Barium / Q000378:metabolism; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008536:Meglumine; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000235:genetics; D010179:Pancreas / Q000166:cytology / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D024483:Vitamin K 3 / Q000494:pharmacology
D053496:Inositol 1,4,5-Trisphosphate Receptors; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C501841:caloxin 3A1; C052617:Bcl2 protein, mouse; D001464:Barium; D008536:Meglumine; D024483:Vitamin K 3; D017301:Ca(2+) Mg(2+)-ATPase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium