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P2X(7) nucleotide receptors mediate caspase-8/9/3-dependent apoptosis in rat primary cortical neurons

Qiongman Kong1, Min Wang, Zhongji Liao

  • 1Interdisciplinary Neuroscience Program, University of Missouri-Columbia, Columbia, Missouri, USA.

Purinergic Signalling
|April 12, 2008
PubMed

Insights

Activation of the P2X(7) receptor (P2X(7)R) triggers apoptosis in rat neurons. This cell death pathway involves caspase-8/9/3 activation and signaling via JNK1 and ERK, highlighting P2X(7)R

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Apoptosis, or programmed cell death, is crucial for nervous system development and implicated in neurodegenerative diseases.
  • Extracellular nucleotides acting via P2X(7) receptors (P2X(7)R) are increasingly recognized for their role in neuronal function and pathology.

Purpose of the Study:

  • To investigate the role of P2X(7)R activation in inducing apoptosis in rat primary cortical neurons (rPCNs).
  • To elucidate the specific signaling pathways involved in P2X(7)R-mediated neuronal cell death.

Main Methods:

  • Primary rat cortical neurons were treated with BzATP, a P2X(7)R agonist.
  • Apoptosis was assessed by measuring caspase activation, nuclear condensation, and DNA fragmentation.
  • Pharmacological inhibitors and antisense oligonucleotides targeting P2X(7)R and specific caspases (caspase-3, -8, -9) and kinases (JNK1, ERK1/2) were used.

Main Results:

  • BzATP treatment induced biochemical and morphological hallmarks of apoptosis in rPCNs.
  • P2X(7)R antagonist oxidized ATP (oATP) and P2X(7)R antisense oligonucleotides blocked BzATP-induced apoptosis.
  • Inhibition of caspase-3, caspase-8, JNK1, or ERK1/2 significantly attenuated BzATP-induced neuronal apoptosis.
  • BzATP-induced apoptosis proceeded via an intrinsic pathway involving caspase-8/9/3 activation, modulated by JNK1 and ERK1/2 signaling.

Conclusions:

  • Extracellular nucleotides acting through P2X(7)Rs are potent inducers of apoptosis in cortical neurons.
  • The P2X(7)R-mediated apoptotic pathway involves the activation of caspases 8/9/3 and the kinases JNK1 and ERK1/2.
  • These findings identify P2X(7)R as a key mediator of neuronal cell death, relevant to neurodevelopment and neurodegenerative conditions.

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