P2X7 nucleotide receptors mediate caspase-8/9/3-dependent apoptosis in rat primary cortical neurons |
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Authors: | Qiongman Kong Min Wang Zhongji Liao Jean M Camden Sue Yu Agnes Simonyi Grace Y Sun Fernando A Gonzalez Laurie Erb Cheikh I Seye Gary A Weisman |
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Institution: | (1) Interdisciplinary Neuroscience Program, University of Missouri-Columbia, Columbia, Missouri, USA;(2) Department of Biochemistry, University of Missouri-Columbia, Missouri, USA;(3) Department of Chemistry, Rio Piedras Campus, University of Puerto-Rico, San Juan, Puerto Rico;(4) Department of Biochemistry, University of Missouri-Columbia, 540E Life Sciences Center, 1201 Rollins Road, Columbia, MO 65211-7310, USA |
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Abstract: | Apoptosis is a major cause of cell death in the nervous system. It plays a role in embryonic and early postnatal brain development
and contributes to the pathology of neurodegenerative diseases. Here, we report that activation of the P2X7 nucleotide receptor (P2X7R) in rat primary cortical neurons (rPCNs) causes biochemical (i.e., caspase activation) and morphological (i.e., nuclear
condensation and DNA fragmentation) changes characteristic of apoptotic cell death. Caspase-3 activation and DNA fragmentation
in rPCNs induced by the P2X7R agonist BzATP were inhibited by the P2X7R antagonist oxidized ATP (oATP) or by pre-treatment of cells with P2X7R antisense oligonucleotide indicating a direct involvement of the P2X7R in nucleotide-induced neuronal cell death. Moreover, Z-DEVD-FMK, a specific and irreversible cell permeable inhibitor of
caspase-3, prevented BzATP-induced apoptosis in rPCNs. In addition, a specific caspase-8 inhibitor, Ac-IETD-CHO, significantly
attenuated BzATP-induced caspase-9 and caspase-3 activation, suggesting that P2X7R-mediated apoptosis in rPCNs occurs primarily through an intrinsic caspase-8/9/3 activation pathway. BzATP also induced the
activation of C-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated kinases (ERK1/2) in rPCNs, and pharmacological
inhibition of either JNK1 or ERK1/2 significantly reduced caspase activation by BzATP. Taken together, these data indicate
that extracellular nucleotides mediate neuronal apoptosis through activation of P2X7Rs and their downstream signaling pathways involving JNK1, ERK and caspases 8/9/3. |
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Keywords: | apoptosis ATP BzATP caspase P2X7 receptor |
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