Figure 1.

Purinergic receptors as well as ATP release mechanisms participating in neuron-astrocyte-microglia cross-talk. Microglia possess the ligand-gated P2X4 and P2X7 receptor subtypes as well as all subtypes of the G protein-coupled P1 (A1, A2A, A2B, A3) receptors. In addition, microglia release ATP from synaptic/lysosomal vesicles via exocytosis but also via connexin (mainly Cx43) channels and pannexin (Panx-1) hemichannels. P2X4 receptor (R) activation induces the vesicular release of brain-derived neurotrophic factor (BDNF), which causes neuropathic pain in the dorsal horn spinal cord. P2X7R activation results in the outward blebbing of the microglial plasma membrane and the production of extracellular vesicles containing interleukin-1β (IL-1β). The pro-inflammatory cytokines IL-1β and tumor necrosis factor-α (TNFα) bind to their receptors IL-1R and TNFαR, respectively. P2X7R activation induces the diffusion of reactive oxygen species (ROS) through the plasma membrane. All these microglial products cause neuroinflammation and neurodegeneration. Exocytotic, Ca²⁺-dependent, vesicular release occurs from neurons, astrocytes, and microglia. The vesicular release of ATP from neurons is much faster than that from astrocytes or microglia, although the vesicular proteins involved in exocytosis are relatively similar in the three cell types. ATP is rapidly degraded by ecto-nucleotidases to ADP, AMP, and eventually by 5’-nucleotidase to the bioactive adenosine (ADO). Artwork by Dr. Haiyan Yin.