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

• Published in: Cell reports (Cambridge) 2023-10, Vol.42 (10), p.113128, Article 113128
• Main Authors: Weilinger, Nicholas L., Yang, Kai, Choi, Hyun B., Groten, Christopher J., Wendt, Stefan, Murugan, Madhuvika, Wicki-Stordeur, Leigh E., Bernier, Louis-Philippe, Velayudhan, Prashanth S., Zheng, Jiaying, LeDue, Jeffrey M., Rungta, Ravi L., Tyson, John R., Snutch, Terrance P., Wu, Long-Jun, MacVicar, Brian A.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; ATP release; Cell Death; Connexins - metabolism; CP: Molecular biology; CP: Neuroscience; cytotoxic edema; microglia; Microglia - metabolism; neuroprotection; P2Y12; pannexin-1; reactive oxygen species; Reactive Oxygen Species - metabolism; ROS; swelling
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113128

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. [Display omitted] •Neuronal swelling in edema leads to cytosolic ROS generation•ROS activates neuronal Panx1 channels with dichotomous consequences•Panx1 activation in swelling causes ionic dysregulation and neuronal death•ATP release via Panx1 increases microglia-neuron contacts that are protective Neuronal death during brain swelling is shown by Weilinger et al. to be caused by ROS-dependent activation of large-pore Panx1 channels. Panx1 opening during neuronal swelling also leads to ATP release that increases neuroprotective microglia-neuron contacts.