title: Biphasic regulation of InsP3 receptor gating by dual Ca2+ release channel BH3-like domains mediates Bcl-xL control of cell viability.
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.
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014;
authors.forename: Horia
authors.initials: H
authors.lastname: Vais
authors.affiliation: Key Laboratory of Reproduction Regulation of the National Population and Family Planning Commission, Shanghai Institute of Planned Parenthood Research, Shanghai 200032, China;
authors.forename: Wenen
authors.initials: W
authors.lastname: Gu
authors.affiliation: 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.
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D051381:Rats; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; C494813:Bcl2l1 protein, rat; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D002118:Calcium
keywords: Bcl-2; apoptosis; calcium; ion channel; mitochondria