Adinolfi Elena, Callegari Maria Giulia, Cirillo Maria, Pinton Paolo, Giorgi Carlotta, Cavagna Dario, Rizzuto Rosario, Di Virgilio Francesco
Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation, University of Ferrara, via Borsari 46, 44100 Ferrara, Italy.
J Biol Chem. 2009 Apr 10;284(15):10120-8. doi: 10.1074/jbc.M805805200. Epub 2009 Feb 9.
The P2X(7) receptor is known for the cytotoxic activity because of its ability to cause opening of non-selective pores in the plasma membrane and activate apoptotic caspases. A key factor of P2X(7)-dependent cytotoxicity is the massive intracellular Ca(2+) increase triggered by its activation. Here we show that P2X(7) transfection increased the ability of the endoplasmic reticulum to accumulate, store, and release Ca(2+). This caused a larger agonist-stimulated increase in cytosol and mitochondrial Ca(2+) in P2X(7) transfectants than in mock transfected cells. P2X(7) transfectants survived and even proliferated in serum-free conditions and were resistant to apoptosis triggered by ceramide, staurosporin, or intracellular Zn(2+) chelation. Finally, the nuclear factor of activated T cells complex 1 (NFATc1) was strongly activated in the P2X(7) transfectants. These observations support our previous finding that the P2X(7) receptor under tonic conditions of stimulation, i.e. those observed in response to basal ATP release, has an anti-apoptotic or even growth promoting rather than cytotoxic activity.
P2X(7)受体因其能够导致质膜上非选择性孔道开放并激活凋亡半胱天冬酶而具有细胞毒性活性。P2X(7)依赖性细胞毒性的一个关键因素是其激活引发的大量细胞内Ca(2+)增加。在此我们表明，P2X(7)转染增强了内质网积累、储存和释放Ca(2+)的能力。这导致与mock转染细胞相比，P2X(7)转染细胞中激动剂刺激引起的胞质溶胶和线粒体Ca(2+)增加更大。P2X(7)转染细胞在无血清条件下存活甚至增殖，并且对神经酰胺、星形孢菌素或细胞内Zn(2+)螯合引发的凋亡具有抗性。最后，活化T细胞核因子复合物1 (NFATc1)在P2X(7)转染细胞中被强烈激活。这些观察结果支持了我们之前的发现，即在持续性刺激条件下，即对基础ATP释放的反应中观察到的那些条件下，P2X(7)受体具有抗凋亡甚至促生长而非细胞毒性活性。
