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Sustained activation of P2X7 induces MMP-2- evoked cleavage and functional purinoceptor inhibition

Journal of Molecular Cell Biology 2018年第3期10卷 229-242页

作者： Christopher N. J. Young Natalia Chira Justyna Róg Rasha Al-Khalidi Magalie Benard Ludovic Galas Philippe Chan David Vaudry Krzysztof Zablocki Dariusz C. Górecki School of Allied Health Sciences Faculty of Health and Life Sciences De Montfort University Leicester LE1 5RR UK Molecular Medicine Laboratory Institute of Biomedical and Biomolecular Sciences School of Pharmacy and Biomedical Sciences University of Portsmouth Portsmouth PO1 2DT UK Laboratory of Cellular Metabolism Department of Biochemistry Nencki Institute of Experimental Biology of the Polish Academy of Sciences Pasteur Str. 02- 093 Warsaw Poland primacen Cell Imaging Platform of Normandy Inserm IBiSA and PISSARO Proteomic Platform Institute for Research and Innovation in Biomedicine University of Rouen 76821 Mont-Saint-Aignan France

P2X7 purinoceptor promotes survival or cytotoxicity depending on extraceUular adenosine triphosphate （ATP） stimulus Intensity controlling its ion channel or P2X7-dependent large pore （LP） functions. Mechanisms governing this operational divergence and functional idiosyncrasy are ill-understood. We have discovered a feedback loop where sustained activation of P2X7 triggers release of active matrix metalloproteinase 2 （MMP-2）, which halts ion channel and LP responses via the MMP-2-dependent receptor cleavage. This mechanism operates in cells as diverse as macrophages, dystrophic myoblasts, P2X7-transfected HEK293, and human tumour cells. Given that serum-born MMP-2 activity also blocked receptor functions, P2X7 responses in vivo may decrease in organs with permeable capillaries. Therefore, this mechanism represents an Important fine-tuning of P2X7 functions, reliant on both cell-autonomous and extraneous factors. Indeed, it allowed evasion from the ATP-induced cvtotoxicity in macrophages and human cancer ceils with high P2X7 expression levels. Finally, we demonstrate that P2X7 ablation eliminated getatinase activity in inflamed dystrophic muscles in vivo. Thus, P2X7 antagonists could be used as an alternative to highly toxic MMP inhibitors in treatments of inflammatory diseases and cancers.

关键词： P2X7 MMP-2 DMD macrophage β-dystroglycan CD44 cancer

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