P2X7 nucleotide receptors mediate caspase-8/9/3-dependent apoptosis in rat primary cortical neurons

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

Research output: Contribution to journalArticle

44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)337-347
Number of pages11
JournalPurinergic Signalling
Volume1
Issue number4
DOIs
StatePublished - Dec 1 2005
Externally publishedYes

Keywords

  • ATP
  • Apoptosis
  • BzATP
  • Caspase
  • P2X receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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    Kong, Q., Wang, M., Liao, Z., Camden, J. M., Yu, S., Simonyi, A., Sun, G. Y., Gonzalez, F. A., Erb, L., Seye, C. I., & Weisman, G. A. (2005). P2X7 nucleotide receptors mediate caspase-8/9/3-dependent apoptosis in rat primary cortical neurons. Purinergic Signalling, 1(4), 337-347. https://doi.org/10.1007/s11302-005-7145-5