P2RX7

Structure and kinetics

The P2X₇ subunits can form homomeric receptors only with a typical P2X receptor structure. The P2X₇ receptor is a ligand-gated cation channel that opens in response to ATP binding and leads to cell depolarization. The P2X₇ 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-D-glucamine (NMDG⁺). P2X₇ receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude.

Agonists

P2X₇ receptors respond to BzATP more readily than ATP. ADP and AMP are weak agonists of P2X₇ receptors, but a brief exposure to ATP can increase their effectiveness.

Antagonists

The P2X₇ receptor current can be blocked by zinc, calcium, magnesium, and copper. P2X₇ receptors are sensitive to pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and relatively insensitive to suramin, but the suramin analog, NF279, is much more effective. Other blockers include the large organic cations calmidazolium (a calmodulin antagonist) and KN-62 (a CaM kinase II antagonist).

Receptor trafficking

In microglia, P2X₇ 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 P2X₇ gene expression may be regulated by MITF.

Recruitment of pannexin

Activation of the P2X₇ 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.

Neuropathic pain

Microglial P2X₇ receptors are thought to be involved in neuropathic pain because blockade or deletion of P2X₇ receptors results in decreased responses to pain, as demonstrated in vivo. Moreover, P2X₇ receptor signaling increases the release of proinflammatory molecules such as IL-1β, IL-6, and TNF-α. In addition, P2X₇ receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3. Interestingly, P2X₇ receptors are also linked to P2X₄ receptors, which are also associated with neuropathic pain mediated by microglia.

Osteoporosis

Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.

Diabetes

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.

Possible link to hepatic fibrosis

One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.