Biphasic regulation of InsP3 receptor gating by dual Ca2+ release channel BH3-like domains mediates Bcl-xL control of cell viability.
Antiapoptotic Bcl-2 family members interact with inositol trisphosphate receptor (InsP3R) Ca(2+)release channels in the endoplasmic reticulum to modulate Ca(2+)signals that affect cell viability. However, the molecular details and consequences of their interactions are unclear. Here, we found that Bcl-xL activates single InsP3R channels with a biphasic concentration dependence. The Bcl-xLBcl-2 homology 3 (BH3) domain-binding pocket mediates both high-affinity channel activation and low-affinity inhibition. Bcl-xL activates channel gating by binding to two BH3 domain-like helices in the channel carboxyl terminus, whereas inhibition requires binding to one of them and to a previously identified Bcl-2 interaction site in the channel-coupling domain. Disruption of these interactions diminishes cell viability and sensitizes cells to apoptotic stimuli. Our results identify BH3-like domains in an ion channel and they provide a unifying model of the effects of antiapoptotic Bcl-2 proteins on the InsP3R that play critical roles in Ca(2+) signaling and cell viability.
['Yang|Jun|J|', 'Vais|Horia|H|', 'Gu|Wenen|W|', 'Foskett|J Kevin|JK|']
D000595:Amino Acid Sequence D000818:Animals D001665:Binding Sites D002118:Calcium D002460:Cell Line D002470:Cell Survival D006801:Humans D053496:Inositol 1,4,5-Trisphosphate Receptors D015640:Ion Channel Gating D061986:MCF-7 Cells D008969:Molecular Sequence Data D017434:Protein Structure, Tertiary D051381:Rats D051028:bcl-2-Associated X Protein D051020:bcl-X Protein
Bcl-2 ion channel apoptosis calcium mitochondria