Astrocytic and Oligodendrocytic P2X7 Receptors Determine Neuronal Functions in the CNS

Abstract

P2X7 receptors are members of the ATP-gated cationic channel family with a preferential localization at the microglial cells, the resident macrophages of the brain. However, these receptors are also present at neuroglia (astrocytes, oligodendrocytes) although at a considerably lower density. They mediate necrosis/apoptosis by the release of pro-inflammatory cytokines/chemokines, reactive oxygen species (ROS) as well as the excitotoxic (glio)transmitters glutamate and ATP. Besides mediating cell damage i.e., superimposed upon chronic neurodegenerative processes in Alzheimer’s Disease, Parkinson’s Disease, multiple sclerosis, and amyotrophic lateral sclerosis, they may also participate in neuroglial signaling to neurons under conditions of high ATP concentrations during any other form of neuroinflammation/neurodegeneration. It is a pertinent open question whether P2X7Rs are localized on neurons, or whether only neuroglia/microglia possess this receptor-type causing indirect effects by releasing the above-mentioned signaling molecules. We suggest as based on molecular biology and functional evidence that neurons are devoid of P2X7Rs although the existence of neuronal P2X7Rs cannot be excluded with absolute certainty.

Botulinum Toxin A Ameliorates Neuroinflammation in the MPTP and 6-OHDA-Induced Parkinson's Disease Models

“…Astrocytic and oligodendrocytic P2X7 receptors mediate some of important neuronal functions in the CNS. For example, they mediate necrosis/apoptosis by releasing proinflammatory cytokines/chemokines, reactive oxygen species (ROS), and the excitotoxic (glio) transmitters glutamate and ATP (Liu and Bing, 2011;Zhao et al, 2021). The microglial phagocytosis of neurons causes neurodegenerative diseases including PD (Butler et al, 2021).…”

Ion Channel Dysfunction in Astrocytes in Neurodegenerative Diseases

“…However, astrocytes lack NLRP3 and thus activation of their P2X7R cannot result in an NLRP3-mediated immunoreaction. Despite the lower density of P2X7R in astrocytes compared to microglia, coupled with astrocytic NLRP3 deficiency, P2X7R-mediated Ca 2+ influx and K + efflux can still activate astrocytes, resulting in the release of glutamate and inflammatory factors that cause excitotoxicity and neurotoxicity ( Illes, 2020 ; Zhao et al, 2021 ).…”

“…Water channel protein aquaporin (AQP) 4 channels are located on astrocyte terminal protrusions, and mediate transfer between cerebrospinal fluid (CSF) and intercellular fluid ( Iliff et al, 2012 ). In addition, astrocytes have a multi-ion transport channel P2X7 receptor (P2X7R), which is sensitive to ATP and permeable to sodium ion (Na + ), K + and Ca 2+ ( Zhao et al, 2021 ). In conclusion, these ion channels regulate astrocytic function by moderating ion homeostasis in astrocytes, while their homeostatic role on extracellular ions and related derivative effects maintain the normal physiological status of the CNS.…”

“…Excessive Ca 2+ not only causes astrogliosis, but also induces KCa3.1 channels to generate more pro-inflammatory factors ( Bouhy et al, 2011 ). The ionic disturbance of astrocytes is not only reflected in the above channels, but P2X7R can also cause an imbalance of Ca 2+ and K + , resulting in overactivation of astrocytes ( Zhao et al, 2021 ). What is more, deficiencies in K-ATP and Kir channels not only cause an imbalance of K + , but a loss of their protective effects leads to astrocyte swelling as a result of the decreased permeability of gap junctions ( Bataveljić et al, 2012 ; Tinker et al, 2018 ).…”

Targeting Neuroinflammation via Purinergic P2 Receptors for Disease Modification in Drug-Refractory Epilepsy

“…P2X 7 expression has also been reported on oligodendrocytes and endothelial cells. 97,98 Its expression and function with regard to astrocytes and neurons remains, however, controversial. 99,100 The metabotropic P2Y-receptor family consists of eight G protein-coupled receptors -P2Y 1,2,4,6,11-14 .…”