Apoptosis regulation by Bcl-x L modulation of mammalian inositol 1,4,5-trisphosphate receptor channel isoform gating

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Abstract
Members of the Bcl-2 family of proteins regulate apoptosis, with some of their physiological effects mediated by their modulation of endoplasmic reticulum (ER) Ca 2+ homeostasis. Antiapoptotic Bcl-x L binds to the inositol trisphosphate receptor (InsP 3 R) Ca 2+ release channel to enhance Ca 2+ - and InsP 3 -dependent regulation of channel gating, resulting in reduced ER [Ca 2+ ], increased oscillations of cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ), and apoptosis resistance. However, it is controversial which InsP 3 R isoforms mediate these effects and whether reduced ER [Ca 2+ ] or enhanced [Ca 2+ ] i signaling is most relevant for apoptosis protection. DT40 cell lines engineered to express each of the three mammalian InsP 3 R isoforms individually displayed enhanced apoptosis sensitivity compared with cells lacking InsP 3 R. In contrast, coexpression of each isoform with Bcl-x L conferred enhanced apoptosis resistance. In single-channel recordings of channel gating in native ER membranes, Bcl-x L increased the apparent sensitivity of all three InsP 3 R isoforms to subsaturating levels of InsP 3 . Expression of Bcl-x L reduced ER [Ca 2+ ] in type 3 but not type 1 or 2 InsP 3 R-expressing cells. In contrast, Bcl-x L enhanced spontaneous [Ca 2+ ] i signaling in all three InsP 3 R isoform-expressing cell lines. These results demonstrate a redundancy among InsP 3 R isoforms in their ability to sensitize cells to apoptotic insults and to interact with Bcl-x L to modulate their activities that result in enhanced apoptosis resistance. Furthermore, these data suggest that modulation of ER [Ca 2+ ] is not a specific requirement for ER-dependent antiapoptotic effects of Bcl-x L . Rather, apoptosis protection is conferred by enhanced spontaneous [Ca 2+ ] i signaling by Bcl-x L interaction with all isoforms of the InsP 3 R.