Pleiotropic Roles of P2X7 in the Central Nervous System

Abstract

The purinergic receptor P2X7 is expressed in neural and immune cells known to be involved in neurological diseases. Its ligand, ATP, is a signaling molecule that can act as a neurotransmitter in physiological conditions or as a danger signal when released in high amount by damaged/dying cells or activated glial cells. Thus, ATP is a danger-associated molecular pattern. Binding of ATP by P2X7 leads to the activation of different biochemical pathways, depending on the physiological or pathological environment. The aim of this review is to discuss various functions of P2X7 in the immune and central nervous systems. We present evidence that P2X7 may have a detrimental or beneficial role in the nervous system, in the context of neurological pathologies: epilepsy, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, age-related macular degeneration and cerebral artery occlusion.

Keywords: ATP; P2X7; animal model; demyelinating disease; nervous system; neurodegenerative disease; neurologic disease; purinergic receptor.

FIGURE 1

P2X7 activation induces cell death via different molecular pathways depending on the cell type. In mouse thymocytes, P2X7 stimulation induces P2X7-dependent pore formation and a calcium-independent cell lysis via the successive activation of a SRC family tyrosine kinase, a phosphatidylinositol 3-kinase, the mitogen-activated protein (MAP) kinase (ERK/2) module, and the proteasome (Auger et al., 2005). In embryonic mouse NPCs, activation of P2X7 does not lead to pore formation but induces mitochondrial membrane depolarization leading to calcium-independent lysis of the cell (Delarasse et al., 2009). High concentration of ATP induces P2X7-dependent pore formation in mouse adult NPCs and activation of caspase 3 leading to cell death (Messemer et al., 2013). P2X7 stimulation induces apoptosis in embryonic rat cortical neurons via activation of the signaling pathways JNK1, ERK and caspases 8/9/3 (Kong et al., 2005). In newborn mouse microglia, P2X7 stimulation induces dephosphorylation of AKT, ERK1/2 and cell death (He et al., 2017). PI: Pharmacological inhibitors were used to specifically inhibit P2X7 or each down-stream enzyme of the pathway. Each of them were able to block P2X7-dependent cell death. KO: Cells from P2X7ko mice were used to analyze P2X7-dependent cell death pathway compared to cells from WT mice.

FIGURE 2

P2X7 stimulation induces NLRP3 activation leading to IL-1β release. Maturation of IL-1β requires 4 signals: 1) TLR activation triggering pro-IL-1β transcription, 2) Ca²⁺ and Na⁺ influxes via P2X7 stimulation leading to activation of TWIK2, 3) K⁺ efflux via P2X7 and TWIK2 leading to NEK7 binding to leucine rich domain of NLRP3, 4) Potential translocation of CLICs to the plasma membrane and Cl^– efflux and activation of NLRP3. NLRP3 oligomerization recruits ASC and induces pro-caspase 1 cleavage leading to the cleavage of pro-IL-1β in mature IL-1β. Several pathways have been described for IL-1β release via exosomes, secretory lysosomes and microvesicles. However, the identification of GSDMD as a substrate of caspase 1 unraveled the role of the GSDMD-N domain in pore formation and pyroptotic cell death.

FIGURE 3

P2X7 plays different roles depending on the cell type that expresses it: Neural progenitor cell (NPC), microglia/macrophage, astrocyte and lymphocyte. The various functions of P2X7 are listed for each cell type.

FIGURE 4

P2X7 roles in the nervous system in physiological and pathological conditions. Depending on the disease of the nervous system and the progression of the pathology, P2X7 has been involved in different pathways [beneficial (+) or not (–)] that are listed in the diagram.

FIGURE 5

Two main P2X7 isoforms have been described in mouse. A full-length P2X7(A) isoform is expressed by macrophages while the P2X7(K) isoform is expressed by T-cells and presents an alternate NH₂ and first transmembrane domains (depicted in orange). The P2X7(A) isoform is sensitive to ATP only while the P2X7(K) isoform is activated by both ATP or by covalent ADP-ribosylation by the enzyme ART2 in the presence of NAD.