P2X7 Receptor and Extracellular Vesicle Release

Abstract

Extensive evidence indicates that the activation of the P2X₇ receptor (P2X₇R), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated with the release of extracellular vesicles. Through this process, P2X₇R-expressing cells regulate non-classical protein secretion and transfer bioactive components to other cells, including misfolded proteins, participating in inflammatory and neurodegenerative diseases. In this review, we summarize and discuss the studies addressing the impact of P2X₇R activation on extracellular vesicle release and their activities.

Keywords: P2X7 receptor; extracellular vesicles; inflammation; neurodegeneration.

Figure 1

Schematic representation of EV release upon ATP-induced P2X₇R activation. Upon ATP stimulation, P2X₇R activation induces the recruitment of an Src kinase at the C-terminus of the receptor and the activation of ROCK and p38 MAP kinase triggering cytoskeletal reorganization (i.e., MLC and LIMK) and the translocation of A-SMase to the outer leaflet of the plasma membrane. A-SMase hydrolyzes sphingomyelin to ceramide, facilitating blebs’ formation and large EV shedding (route 1). P2X₇R activation and the consequent efflux of K⁺ also promotes the release of small EVs, generated in the endosomal compartment as ILVs, by inducing NLRP3/ASC/procaspase-1 inflammasome assembling. Inflammasome activation regulates the membrane trafficking pathways that control MVB fusion to the plasma membrane via the cleavage of RILP (route 2). Image created with BioRender.com (accessed on 15 March 2023).

Figure 2

Schematic representation of cytokine processing in EVs upon ATP-induced P2X₇R activation. P2X₇R activation, by inducing NLRP3 inflammasome assembling, triggers pro-caspase-1 cleavage, which generates active caspase-1 that, in turn, drives the enzymatic activation of the leaderless pro-inflammatory cytokines IL-1β and IL-18. On the other hand, ATP induces TNF packaging into EVs as a transmembrane pro-TNF isoform. Image created with BioRender.com (accessed on 15 March 2023).