Antiapoptotic Bcl-2 family members interact with inositol trisphosphate receptor (InsP 3 R) 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-x L activates single InsP 3 R channels with a biphasic concentration dependence. The Bcl-x L Bcl-2 homology 3 (BH3) domain-binding pocket mediates both high-affinity channel activation and low-affinity inhibition. Bcl-x L 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 channelcoupling 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 InsP 3 R that play critical roles in Ca 2+ signaling and cell viability.T he inositol trisphosphate receptors (InsP 3 R) are a family of intracellular cation channels that release Ca 2+ from the endoplasmic reticulum (ER) in response to a variety of extracellular stimuli (1). Three InsP 3 R isoforms are ubiquitously expressed and regulate diverse cell processes, including cell viability (1). Activation of the channels by InsP 3 elicits changes in cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ) that provide versatile signals to regulate molecular processes with high spatial and temporal fidelity (1). Regions of close proximity to mitochondria enable localized Ca 2+ release events to be transduced to mitochondria (2, 3). Ca 2+ released from the ER during cell stimulation modulates activities of effector molecules and is taken up by mitochondria to stimulate oxidative phosphorylation and enhance ATP production (4-6) to match energetic supply with enhanced demand. In addition, cells in vivo are constantly exposed to low levels of circulating hormones, transmitters, and growth factors that bind to plasma membrane receptors to provide a background level of cytoplasmic InsP 3 (7) that generates low-level stochastic InsP 3 R-mediated localized or propagating [Ca 2+ ] i signals (8-10). Such signals also play an important role in maintenance of cellular bioenergetics (8). Nevertheless, under conditions of cell stress the close proximity of mitochondria to Ca 2+ release sites may result in mitochondrial Ca 2+ overload and initiate Ca 2+ -dependent forms of cell death, including necrosis and apoptosis (11-13). It has been suggested that high levels of ER Ca 2+ (14-16) and enhanced activity of the InsP 3 R (17-19) promote cell death by providing a higher quantity of released Ca 2+ to mitochondria (3,20,21).Protein interactions modulate the magnitude and quality of InsP 3 R-mediated [Ca 2+ ] i signals that regulate apoptosis and cell viability. Notable in this regard is the Bcl-2 protein family. Proapoptotic Bcl-2-related proteins Bax ...

Experimentally determined octanol-air partition coefficients (K ) for 43 polychlorinated naphthalene (PCN) congeners and experimentally determined subcooled liquid vapor pressures (P) for 17 PCN congeners were used with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to generate three-dimensional quantitative structure-activity relationship (3D-QSAR) models. The data were used to predict K values for the other 32 congeners and P values for the other 58 congeners. The CoMFA and CoMSIA model contour maps showed that the electrostatic fields of the PCN molecules are the most important factors affecting the K and P values. The long-range transport potentials of several PCN homologs were assessed using the following grading system: high mobility (MoCNs), relatively high mobility (DiCNs to TeCNs), relatively low mobility (PeCNs to HeCNs) and low mobility (HeCNs and OCN). The PCN-2 molecule was modified using the contour maps of the two models, and the results showed that introducing an electronegative R substituent increased the K value but introducing an electropositive R substituent decreased the P value. PCN-2 was in the high mobility class, but introducing these substituents moved the long-range transport potentials of the modified molecules to the relatively high mobility class.