Synergistic movements of Ca(2+) and Bax in cells undergoing apoptosis.
Apoptosis is a physiological counterbalance to mitosis and plays important roles in tissue development and homeostasis. Cytosolic Ca(2+) has been implicated as a proapoptotic second messenger involved in both triggering apoptosis and regulating cell death-specific enzymes. A critical early event in apoptosis is associated with the redistribution of Bax from cytosol to mitochondria and endoplasmic reticulum (ER) membranes; however, the molecular mechanism of Bax translocation and its relationship to Ca(2+) is largely unknown. Here we provide functional evidence for a synergistic interaction between the movements of intracellular Ca(2+) and cytosolic Bax in the induction of apoptosis. Overexpression of Bax in cultured cells causes a loss of ER Ca(2+) content. Depletion of ER Ca(2+) through activation of the ryanodine receptor enhances the participation of Bax into the mitochondrial membrane. Neither Bax translocation nor Bax-induced apoptosis is affected by buffering of cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, suggesting that depletion of ER Ca(2+) rather than elevation of cytosolic Ca(2+) is the signal for cell apoptosis. This dynamic interplay of Ca(2+) and Bax movements may serve as an amplifying factor in the initial signaling steps of apoptosis.
Pan
Z
Z
Departments of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Bhat
M B
MB
Nieminen
A L
AL
Ma
J
J
D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D004533:Egtazic Acid / Q000031:analogs & derivatives; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006706:Homeostasis; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D018613:Microscopy, Confocal; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D014162:Transfection; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D007202:Indicators and Reagents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019837:Ryanodine Receptor Calcium Release Channel; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004533:Egtazic Acid; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium