P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.
The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced variants which would encode different isoforms have been identified although some fit nonsense-mediated decay criteria.
The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, in uterine endometrium, and in the retina. The P2X<SUB>7</SUB> receptor also serves as a pattern recognition receptor for extracellular ATP-mediated apoptotic cell death, regulation of receptor trafficking, mast cell degranulation, and inflammation. Regarding inflammation, P2X7 receptor induces the NLRP3 inflammasome in myeloid cells and leads to interleukin-1beta release.
The P2X<SUB>7</SUB> subunits can form homomeric receptors only with a typical P2X receptor structure. The P2X<SUB>7</SUB> receptor is a ligand-gated cation channel that opens in response to ATP binding and leads to cell depolarization. The P2X<SUB>7</SUB> receptor requires higher levels of ATP than other P2X receptors; however, the response can be potentiated by reducing the concentration of divalent cations such as calcium or magnesium. Continued binding leads to increased permeability to N-methyl-<small>D</small>-glucamine (NMDG<sup>+</sup>). P2X<SUB>7</SUB> receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude.
In microglia, P2X<SUB>7</SUB> receptors are found mostly on the cell surface. Conserved cysteine residues located in the carboxyl terminus seem to be important for receptor trafficking to the cell membrane. These receptors are upregulated in response to peripheral nerve injury.
In melanocytic cells P2X<sub>7</sub> gene expression may be regulated by MITF.
Activation of the P2X<sub>7</sub> receptor by ATP leads to recruitment of pannexin pores which allow small molecules such as ATP to leak out of cells. This allows further activation of purinergic receptors and physiological responses such a spreading cytoplasmic waves of calcium. Moreover, this could be responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to larger molecules.
On T cells activation of P2X<SUB>7</SUB> receptors can activate the T cells or cause T cell differentiation, can affect T cell migration or (at high extracellular levels of ATP and/or NAD+) can induce cell death. The CD38 enzyme on B lymphocytes and macrophages reduces extracellular NAD+, promoting the survival of T cells.
Microglial P2X<SUB>7</SUB> receptors are thought to be involved in neuropathic pain because blockade or deletion of P2X<SUB>7</SUB> receptors results in decreased responses to pain, as demonstrated in vivo. Moreover, P2X<SUB>7</SUB> receptor signaling increases the release of proinflammatory molecules such as IL-1ò, IL-6, and TNF-ñ. In addition, P2X<SUB>7</SUB> receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3. P2X<SUB>7</SUB> receptors are also linked to P2X<SUB>4</SUB> receptors, which are also associated with neuropathic pain mediated by microglia.
Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.
The ATP/P2X7R pathway may trigger T-cell attacks on the pancreas, rendering it unable to produce insulin. This autoimmune response may be an early mechanism by which the onset of diabetes is caused.
One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.