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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-07, Vol.104 (30), p.12565-12570
• Main Authors: Li, Chi, Wang, Xiaoli, Vais, Horia, Thompson, Craig B, Foskett, J. Kevin, White, Carl
• Format: Article
• Language: English
• Subjects: Biological Sciences
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0702489104

Members of the Bcl-2 family of proteins regulate apoptosis, with some of their physiological effects mediated by their modulation of endoplasmic reticulum (ER) Ca²⁺ homeostasis. Antiapoptotic Bcl-xL binds to the inositol trisphosphate receptor (InsP₃R) Ca²⁺ release channel to enhance Ca²⁺- and InsP₃-dependent regulation of channel gating, resulting in reduced ER [Ca²⁺], increased oscillations of cytoplasmic Ca²⁺ concentration ([Ca²⁺]i), and apoptosis resistance. However, it is controversial which InsP₃R isoforms mediate these effects and whether reduced ER [Ca²⁺] or enhanced [Ca²⁺]i signaling is most relevant for apoptosis protection. DT40 cell lines engineered to express each of the three mammalian InsP₃R isoforms individually displayed enhanced apoptosis sensitivity compared with cells lacking InsP₃R. In contrast, coexpression of each isoform with Bcl-xL conferred enhanced apoptosis resistance. In single-channel recordings of channel gating in native ER membranes, Bcl-xL increased the apparent sensitivity of all three InsP₃R isoforms to subsaturating levels of InsP₃. Expression of Bcl-xL reduced ER [Ca²⁺] in type 3 but not type 1 or 2 InsP₃R-expressing cells. In contrast, Bcl-xL enhanced spontaneous [Ca²⁺]i signaling in all three InsP₃R isoform-expressing cell lines. These results demonstrate a redundancy among InsP₃R isoforms in their ability to sensitize cells to apoptotic insults and to interact with Bcl-xL to modulate their activities that result in enhanced apoptosis resistance. Furthermore, these data suggest that modulation of ER [Ca²⁺] is not a specific requirement for ER-dependent antiapoptotic effects of Bcl-xL. Rather, apoptosis protection is conferred by enhanced spontaneous [Ca²⁺]i signaling by Bcl-xL interaction with all isoforms of the InsP₃R.