Sustained activation of P2X7 induces MMP-2-evoked cleavage and functional purinoceptor inhibition. (11th September 2017)

• Record Type: Journal Article
• Authors: Young, Christopher N J; Chira, Natalia; Róg, Justyna; Al-Khalidi, Rasha; Benard, Magalie; Galas, Ludovic; Chan, Philippe; Vaudry, David; Zabłocki, Krzysztof; Górecki, Dariusz C
• Is Part Of: Journal of molecular cell biology. Volume 10:Number 3(2018:Jun.)
• Page Start: 229
• Page End: 242
• Publication Date: 2017-09-11
• Subjects: P2X7 -- MMP-2 -- DMD -- macrophage -- β-dystroglycan -- CD44 -- cancer; Molecular biology -- Periodicals; 571.605
• DOI: 10.1093/jmcb/mjx030
• Languages: English
• ISSNs: 1674-2788

Abstract

Abstract: P2X7 purinoceptor promotes survival or cytotoxicity depending on extracellular 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 cytotoxicity in macrophages and human cancer cells with high P2X7 expression levels. Finally, we demonstrate that P2X7 ablation eliminated gelatinase 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.