P2RX7

P2X purinoceptor 7 is a is_associated_with::protein that in humans is encoded by the P2RX7 is_associated_with::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 is_associated_with::nonsense-mediated decay criteria.

The receptor is found in the central and peripheral nervous systems, in is_associated_with::microglia, in is_associated_with::macrophages, in uterine is_associated_with::endometrium, and in the is_associated_with::retina. P2X7 receptors have been implicated in ATP-mediated cell death, regulation of receptor trafficking, and is_associated_with::inflammation.

Structure and kinetics
The P2X7 subunits can form is_associated_with::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 is_associated_with::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 is_associated_with::calcium or is_associated_with::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 is_associated_with::zinc, is_associated_with::calcium, is_associated_with::magnesium, and is_associated_with::copper. P2X7</SUB> receptors are sensitive to pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (is_associated_with::PPADS) and relatively insensitive to is_associated_with::suramin, but the suramin analog, NF279, is much more effective. Other blockers include the large organic cations calmidazolium (a is_associated_with::calmodulin antagonist) and is_associated_with::KN-62 (a CaM kinase II antagonist).

Receptor trafficking
In is_associated_with::microglia, P2X7</SUB> receptors are found mostly on the cell surface. Conserved is_associated_with::cysteine residues located in the is_associated_with::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 is_associated_with::pannexin pores which allow small molecules such as ATP to leak out of cells. This allows further activation of is_associated_with::purinergic receptors and physiological responses such a spreading cytoplasmic waves of calcium. Moreover, this could be responsible for ATP-dependent lysis of is_associated_with::macrophages through the formation of membrane pores permeable to larger molecules.

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

Possible link to diabetes
Paolo Fiorina, MD, PhD, of the Nephrology Division at Boston Children’s Hospital and his team studied hundreds of pathways in animals with diabetes. They eventually isolated one, known as ATP/P2X7R, which triggers the T-cell attacks on the pancreas, rendering it unable to produce insulin.

“By identifying the ATP/P2X7R pathway as the early mechanism in the body that fires up an autoimmune response, we found the root cause of is_associated_with::diabetes” says Fiorina.

Possible link to hepatic fibrosis
One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.