P2RX7

The P2X₇ subunits can form homomeric receptors only with a typical P2X receptor structure.^[24] 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.^[8][25] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG⁺).^[25] P2X₇ receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude.^[25]

• P2X₇ receptors respond to BzATP more readily than ATP.^[25]
• ADP and AMP are weak agonists of P2X₇ receptors, but a brief exposure to ATP can increase their effectiveness.^[25]
• Glutathione has been proposed to act as a P2X₇ receptor agonist when present at milimolar levels, inducing calcium transients and GABA release from retinal cells.^[10][9]

• The P2X₇ receptor current can be blocked by zinc, calcium, magnesium, and copper.^[25]
• 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.
• Oxidized ATP (OxATP) and Brilliant Blue G has also been used for blocking P2X₇ in inflammation.^[26][27]
• Other blockers include the large organic cations calmidazolium (a calmodulin antagonist) and KN-62 (a CaM kinase II antagonist).^[25]
• JNJ-54175446 and JNJ-55308942 are selective antagonists

In microglia, P2X₇ receptors are found mostly on the cell surface.^[28] Conserved cysteine residues located in the carboxyl terminus seem to be important for receptor trafficking to the cell membrane.^[29] These receptors are upregulated in response to peripheral nerve injury.^[30]

In melanocytic cells P2X₇ gene expression may be regulated by MITF.^[31]

Activation of the P2X₇ receptor by ATP leads to recruitment of pannexin pores^[32] 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.^[33] 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 P2X₇ 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.^[34] The CD38 enzyme on B lymphocytes and macrophages reduces extracellular NAD+, promoting the survival of T cells.^[35]

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.^[36][37] Moreover, P2X₇ receptor signaling increases the release of proinflammatory molecules such as IL-1β, IL-6, and TNF-α.^[38][39][40] In addition, P2X₇ receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3.^[41][42] P2X₇ receptors are also linked to P2X₄ receptors, which are also associated with neuropathic pain mediated by microglia.^[28]

Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.^[43]

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.^[44][45]

One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.^[46]

• Purinergic receptor
• P2X receptor

• P2RX7+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.