Adinolfi Elena, Callegari Maria Giulia, Ferrari Davide, Bolognesi Chiara, Minelli Mattia, Wieckowski Mariusz R, Pinton Paolo, 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, 44100 Ferrara, Italy.
Mol Biol Cell. 2005 Jul;16(7):3260-72. doi: 10.1091/mbc.e04-11-1025. Epub 2005 May 18.
P2X7 is a bifunctional receptor (P2X7R) for extracellular ATP that, depending on the level of activation, forms a cation-selective channel or a large conductance nonselective pore. The P2X7R has a strong proapoptotic activity but can also support growth. Here, we describe the mechanism involved in growth stimulation. Transfection of P2X7R increases resting mitochondrial potential (delta psi(mt)), basal mitochondrial Ca2+ ([Ca2+]mt), intracellular ATP content, and confers ability to grow in the absence of serum. These changes require a full pore-forming function, because they are abolished in cells transfected with a mutated P2X7R that retains channel activity but cannot form the nonselective pore, and depend on an autocrine/paracrine tonic stimulation by secreted ATP. On the other hand, sustained stimulation of P2X7R causes a delta psi(mt) drop, a large increase in [Ca2+]mt, mitochondrial fragmentation, and cell death. These findings reveal a hitherto undescribed mechanism for growth stimulation by a plasma membrane pore.
P2X7是一种细胞外ATP的双功能受体（P2X7R），根据激活水平，它可形成阳离子选择性通道或大电导非选择性孔道。P2X7R具有很强的促凋亡活性，但也能支持细胞生长。在此，我们描述了其参与生长刺激的机制。转染P2X7R可增加静息线粒体膜电位（Δψmt）、基础线粒体Ca2+浓度（[Ca2+]mt）、细胞内ATP含量，并赋予细胞在无血清条件下生长的能力。这些变化需要完整的孔道形成功能，因为在转染了保留通道活性但不能形成非选择性孔道的突变型P2X7R的细胞中，这些变化消失了，并且这些变化依赖于分泌型ATP的自分泌/旁分泌张力刺激。另一方面，持续刺激P2X7R会导致Δψmt下降、[Ca2+]mt大幅增加、线粒体碎片化和细胞死亡。这些发现揭示了一种迄今为止未被描述的通过质膜孔道进行生长刺激的机制。
