Table 1.

Overview of Bcl-2 family functioning in intracellular Ca²⁺ homeostasis and IP₃R-mediated Ca²⁺ signaling at various subcellular localizations

Bcl-2 family protein	Localization	Functioning
Anti-apoptotic
Bcl-2	ER	Mediates ER Ca2+ stores Binds IP3R (type 1, 2, and 3) Reduces IP3R channel activity Enhances IP3R-mediated Ca2+ oscillations
	Mitochondria	Mediates VDAC opening Regulates PTP opening
	Plasma membrane	Mediates CCE through SOC
	Nuclear envelope	Pro-apoptotic functioning Increases nuclear envelope permeability Increases size-exclusion limit of NPC
Bcl-xL	ER	Binds IP3R (type 1, 2, and 3) Diminishes IP3R expression Increases IP3R channel activity Causes an overall decrease in the percentage of ER Ca2+ released
	Mitochondria	Mediates VDAC opening
	Cytosol	N/A
Mcl-1	ER	Reduces ER luminal Ca2+ Binds IP3R (type 1, 2, and 3) Enhances IP3R-mediated Ca2+ oscillations
	Mitochondria	Inhibits Ca2+ uptake
	Cytosol	N/A
HAX-1	ER	Downregulates SERCA2 expression Reduces ER luminal Ca2+ concentration
	Mitochondria	N/A
	Nuclear envelope	N/A
Pro-apoptotic
Bax/Bak	ER	Increases ER luminal Ca2+ concentration Binds IP3R (type 1)
	Mitochondria	Mediates VDAC opening
Bid/tBid	Mitochondria	Mediates VDAC opening
Puma	Mitochondria	Induces cytochrome c release
	Cytosol	Upregulation by ER Ca2+ depletion Expression is necessary for ER stress-induced apoptosis Activates caspases-3, 8 and 9
Bad	Mitochondria	Activates caspase-3
	Cytosol	N/A
Bik	ER	Enhances ER Ca2+ efflux (Bax/Bak-dependent)
BNIP3	ER	Enhances ER Ca2+ efflux
	Mitochondria	Increases Ca2+ uptake Dissipates membrane potential
Nix	ER	Enhances ER Ca2+ efflux Mediates PTP opening
	Mitochondria	N/A