Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 113, Issue 4, Pages 1377-1385Publisher
WILEY-BLACKWELL
DOI: 10.1002/jcb.24010
Keywords
P2X7 RECEPTOR; Ca2+STORE; ENDOPLASMIC RETICULUM STRESS
Categories
Funding
- National Science Council of Taiwan [NSC 100-2320-B-039-006-]
- Hsing Tian Kong Scholarship
- China Medical University Hospital [DMR-97-101]
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P2X7 receptor (P2X7R) activation by extracellular ATP triggers influx of Na+ and Ca2+, cytosolic Ca2+ overload and consequently cytotoxicity. Whether disturbances in endoplasmic reticulum (ER) Ca2+ homeostasis and ER stress are involved in P2X7R-mediated cell death is unknown. In this study, a P2X7R agonist (BzATP) was used to activate P2X7R in differentiated NG108-15 neuronal cells. In a concentration-dependent manner, application of BzATP (10100?mu M) immediately raised cytosolic Ca2+ concentration ([Ca2+]i) and caused cell death after a 24-h incubation. P2X7R activation for 2?h did not cause cell death but resulted in a sustained reduction in ER Ca2+ pool size, as evidenced by a diminished cyclopiazonic acid-induced Ca2+ discharge (fura 2 assay) and a lower fluorescent signal in cells loaded with Mag-fura 2 (ER-specific Ca2+-fluorescent dye). Furthermore, P2X7R activation (2?h) led to the appearance of markers of ER stress [phosphorylated a subunit of eukaryotic initiation factor 2 (p-eIF2a) and C/EBP homologous protein (CHOP)] and apoptosis (cleaved caspase 3). Xestospongin C (XeC), an antagonist of inositol-1,4,5-trisphosphate (IP3) receptor (IP3R), strongly inhibited BzATP-triggered [Ca2+]i elevation, suggesting that the latter involved Ca2+ release via IP3R. XeC pretreatment not only attenuated the reduction in Ca2+ pool size in BzATP-treated cells, but also rescued cell death and prevented BzATP-induced appearance of ER stress and apoptotic markers. These novel observations suggest that P2X7R activation caused not only Ca2+ overload, but also Ca2+ release via IP3R, sustained Ca2+ store depletion, ER stress and eventually apoptotic cell death. J. Cell. Biochem. 113: 13771385, 2012. (c) 2011 Wiley Periodicals, Inc.
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