Jayaraman T, Marks A R
Departments of Medicine, Molecular Cardiology Program, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
J Biol Chem. 2000 Mar 3;275(9):6417-20. doi: 10.1074/jbc.275.9.6417.
The inositol 1,4,5-trisphosphate receptor (IP(3)R) is a calcium (Ca(2+)) release channel found on the endoplasmic reticulum of virtually all types of cells. Human T lymphocytes (Jurkat) that are made deficient in IP(3)R do not generate Ca(2+) signals in response to T cell receptor stimulation, fail to translocate the nuclear factor for activated T cells to the nucleus, and are remarkably resistant to induction of apoptosis with CD95 (Fas), dexamethasone, gamma irradiation, and T cell receptor stimulation using anti-CD3 antibody. Expression of constitutively active calcineurin A in IP(3)R-deficient T cells restored nuclear factor for activated T cells translocation to the nucleus and dephosphorylation of Bad and rendered the cells sensitive to apoptotic inducers. Induction of apoptosis required both active calcineurin A (DeltaCnA) and activation-dependent colocalization of CnA with its substrate. Thus, the Ca(2+)-dependent phosphatase calcineurin (CnA) is downstream of the IP(3)R in both the cell growth and apoptotic signaling pathways.
肌醇1,4,5 -三磷酸受体（IP(3)R）是一种钙（Ca(2+)）释放通道，几乎在所有类型细胞的内质网上都能找到。缺乏IP(3)R的人T淋巴细胞（Jurkat细胞）在受到T细胞受体刺激时不会产生Ca(2+)信号，无法将活化T细胞核因子转运至细胞核，并且对通过CD95（Fas）、地塞米松、γ射线照射以及使用抗CD3抗体进行T细胞受体刺激诱导的凋亡具有显著抗性。在缺乏IP(3)R的T细胞中组成型激活的钙调神经磷酸酶A的表达恢复了活化T细胞核因子向细胞核的转运以及Bad的去磷酸化，并使细胞对凋亡诱导剂敏感。凋亡的诱导既需要活性钙调神经磷酸酶A（DeltaCnA），也需要CnA与其底物的激活依赖性共定位。因此，在细胞生长和凋亡信号通路中，钙依赖性磷酸酶钙调神经磷酸酶（CnA）都位于IP(3)R的下游。
