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

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

Author information

1
Key Laboratory of Reproduction Regulation of the National Population and Family Planning Commission, Shanghai Institute of Planned Parenthood Research, Shanghai 200032, China; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014; junyangsd@yahoo.com foskett@mail.med.upenn.edu.
2
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014;
3
Key Laboratory of Reproduction Regulation of the National Population and Family Planning Commission, Shanghai Institute of Planned Parenthood Research, Shanghai 200032, China;
4
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014 junyangsd@yahoo.com foskett@mail.med.upenn.edu.

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

PMID:
26976600
PMCID:
PMC4822637
DOI:
10.1073/pnas.1517935113
[Indexed for MEDLINE]
Free PMC Article

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