Bcl-2 and calcium: controversy beneath the surface

The function of Bcl-2 family members on the endoplasmic reticulum has received increasing attention in recent years. The endoplasmic reticulum is the major organelle involved in intracellular calcium homeostasis and calcium signaling, including calcium signals that mediate apoptosis induction by anticancer drugs. But currently a controversy exists regarding reported effects of Bcl-2 on the calcium concentration within the lumen of the endoplasmic reticulum. Although several prominent reports indicate that Bcl-2 overexpression is associated with a decrease in luminal calcium, there are a large number of reports indicating that Bcl-2 either does not decrease luminal calcium or actually increases luminal calcium. This review summarizes this vast array of conflicting findings, and analyses potential reasons why different conclusions have been reached by different laboratories. Future directions are emphasized that might bring clarity to this important area of apoptosis biology.