Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum.
Proapoptotic BCL-2 family members BAX and BAK are required for the initiation of mitochondrial dysfunction during apoptosis and for maintaining the endoplasmic reticulum (ER) Ca(2+) stores necessary for Ca(2+)-dependent cell death. Conversely, antiapoptotic BCL-2 has been shown to decrease Ca(2+) concentration in the ER. We found that Bax(-/-)Bak(-/-) double-knockout (DKO) cells have reduced resting ER Ca(2+) levels because of increased Ca(2+) leak and an increase in the Ca(2+)-permeable, hyperphosphorylated state of the inositol trisphosphate receptor type 1 (IP3R-1). The ER Ca(2+) defect of DKO cells is rescued by RNA interference reduction of IP3R-1, supporting the argument that this channel regulates the increased Ca(2+) leak in these cells. BCL-2 and IP3R-1 physically interact at the ER, and their binding is increased in the absence of BAX and BAK. Moreover, knocking down BCL-2 decreases IP3R-1 phosphorylation and ER Ca(2+) leak rate in the DKO cells. These findings support a model in which BCL-2 family members regulate IP3R-1 phosphorylation to control the rate of ER Ca(2+) leak from intracellular stores.
Oakes
Scott A
SA
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Departments of Pathology and Medicine, Harvard Medical School, Boston, MA 02115, USA.
Scorrano
Luca
L
Opferman
Joseph T
JT
Bassik
Michael C
MC
Nishino
Mari
M
Pozzan
Tullio
T
Korsmeyer
Stanley J
SJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D002118:Calcium