Biphasic regulation of InsP3 receptor gating by dual Ca2+ release channel BH3-like domains mediates Bcl-xL control of cell viability

Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):E1953-62. doi: 10.1073/pnas.1517935113. Epub 2016 Mar 14.

Abstract

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.

Keywords: Bcl-2; apoptosis; calcium; ion channel; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Calcium / metabolism
  • Cell Line
  • Cell Survival
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Ion Channel Gating / physiology
  • MCF-7 Cells
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Rats
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism*

Substances

  • BAX protein, human
  • Bcl2l1 protein, rat
  • Inositol 1,4,5-Trisphosphate Receptors
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Calcium