Pannexin-1 opening in neuronal edema causes cell death but also leads to protection via increased microglia contacts

Nicholas L. Weilinger, Kai Yang, Hyun B. Choi, Christopher J. Groten, Stefan Wendt, Madhuvika Murugan, Leigh E. Wicki-Stordeur, Louis Philippe Bernier, Prashanth S. Velayudhan, Jiaying Zheng, Jeffrey M. LeDue, Ravi L. Rungta, John R. Tyson, Terrance P. Snutch, Long Jun Wu, Brian A. MacVicar

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Neuronal swelling during cytotoxic edema is triggered by Na+ and Cl entry and is Ca2+ independent. However, the causes of neuronal death during swelling are unknown. Here, we investigate the role of large-conductance Pannexin-1 (Panx1) channels in neuronal death during cytotoxic edema. Panx1 channel inhibitors reduce and delay neuronal death in swelling triggered by voltage-gated Na+ entry with veratridine. Neuronal swelling causes downstream production of reactive oxygen species (ROS) that opens Panx1 channels. We confirm that ROS activates Panx1 currents with whole-cell electrophysiology and find scavenging ROS is neuroprotective. Panx1 opening and subsequent ATP release attract microglial processes to contact swelling neurons. Depleting microglia using the CSF1 receptor antagonist PLX3397 or blocking P2Y12 receptors exacerbates neuronal death, suggesting that the Panx1-ATP-dependent microglia contacts are neuroprotective. We conclude that cytotoxic edema triggers oxidative stress in neurons that opens Panx1 to trigger death but also initiates neuroprotective feedback mediated by microglia contacts.

Original languageEnglish (US)
Article number113128
JournalCell Reports
Volume42
Issue number10
DOIs
StatePublished - Oct 31 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology

Keywords

  • ATP release
  • CP: Molecular biology
  • CP: Neuroscience
  • P2Y12
  • ROS
  • cytotoxic edema
  • microglia
  • neuroprotection
  • pannexin-1
  • reactive oxygen species
  • swelling

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