Apoptosis regulation by Bcl-xL modulation of mammalian inositol 1,4,5-trisphosphate receptor channel isoform gating
Apoptosis regulation by Bcl-xL modulation of mammalian inositol 1,4,5-trisphosphate receptor channel isoform gating
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DOI：
10.1073/pnas.0702489104
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发表时间：
2007-07-24
影响因子：
11.1
通讯作者：
White, Carl
中科院分区：
文献类型：
--
作者：
Li, Chi;Wang, Xiaoli;White, Carl
Bcl2家族的成员调控细胞凋亡，其部分生理作用是通过调节内质网(ER)内钙稳态来实现的。抗凋亡剂BclX-L与三磷酸肌醇受体(InSP(3)R)钙释放通道结合，增强钙和InSP(3)依赖的通道门控调节，导致内质网[Ca~(2+)]降低，胞浆Ca~(2+)浓度([Ca~(2+)]_i)振荡增加，从而抑制细胞凋亡。然而，Insp(3)R亚型中的哪种亚型介导了这些作用，以及ER[Ca~(2+)]i信号降低还是[Ca~(2+)]i信号增强与细胞凋亡保护最相关，目前仍存在争议。与缺乏Insp(3)R的细胞相比，单独表达3种哺乳动物Insp(3)R亚型的Dt40细胞株表现出更高的凋亡敏感性。相反，与BCI-X-L共表达每种亚型都能增强细胞对凋亡的抵抗力。在天然ER膜通道门控的单通道记录中，BCI-X-L增加了所有三种Insp(3)R亚型对Insp(3)亚饱和水平的表观敏感性。BclX-L的表达降低了3型Insp(3)R表达细胞的内质网[Ca~(2+)]，但不能降低1型或2型Insp(3)R的表达。相反，BCI-X-L增强了三种Insp(3)R亚型表达细胞的自发[Ca~(2+)]，信号转导。这些结果表明，InSP3R亚型之间存在冗余，它们能够使细胞对凋亡损伤敏感，并与BclX-L相互作用，调节它们的活性，从而增强对凋亡的抵抗力。此外，这些数据表明，内质网[Ca~(2+)]的调节并不是BclX-L的ER依赖的抗细胞凋亡作用的特定要求。相反，通过bc1-X-L与Insp(3)R的所有异构体相互作用，增强了自发的[Ca~(2+)]i信号，从而实现了对细胞凋亡的保护。
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-X-L binds to the inositol trisphosphate receptor (InsP(3)R) Ca2+ release channel to enhance Ca2+- and InsP(3)-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 InsP(3)R 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 InsP(3)R isoforms individually displayed enhanced apoptosis sensitivity compared with cells lacking InsP(3)R. In contrast, coexpression of each isoform with BCI-X-L conferred enhanced apoptosis resistance. In single-channel recordings of channel gating in native ER membranes, BCI-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 [Ca2+] in type 3 but not type 1 or 2 InsP(3)R-expressing cells. In contrast, BCI-X-L enhanced spontaneous [Ca2+], signaling in all three InsP(3)R 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-X-L 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-X-L. Rather, apoptosis protection is conferred by enhanced spontaneous [Ca2+]i signaling by BCl-X-L interaction with all isoforms of the InsP(3)R.