P2X purinoceptor 7 is a
protein that in humans is encoded by the P2RX7gene.[5][6]
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.[7]
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]
Pharmacology
Agonists
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]
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]
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]
Recruitment of pannexin
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.
Clinical significance
Inflammation
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]
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.[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]
Osteoporosis
Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.[43]
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.[44][45]
Research
Possible link to hepatic fibrosis
One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.[46]
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^Slater NM, Barden JA, Murphy CR (June 2000). "Distributional changes of purinergic receptor subtypes (P2X 1-7) in uterine epithelial cells during early pregnancy". The Histochemical Journal. 32 (6): 365–72.
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^Freitas HR, Isaac AR, Silva TM, Diniz GO, Dos Santos Dabdab Y, Bockmann EC, et al. (September 2019). "Cannabinoids Induce Cell Death and Promote P2X7 Receptor Signaling in Retinal Glial Progenitors in Culture". Molecular Neurobiology. 56 (9): 6472–6486.
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^Kawano A, Tsukimoto M, Noguchi T, Hotta N, Harada H, Takenouchi T, et al. (March 2012). "Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages". Biochemical and Biophysical Research Communications. 419 (2): 374–80.
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^Kobayashi K, Takahashi E, Miyagawa Y, Yamanaka H, Noguchi K (October 2011). "Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model". Neuroscience Letters. 504 (1): 57–61.
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^Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K, Nakata Y (September 2000). "Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia". Journal of Neurochemistry. 75 (3): 965–72.
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