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]
^Buell GN, Talabot F, Gos A, Lorenz J, Lai E, Morris MA, Antonarakis SE (Feb 1999). "Gene structure and chromosomal localization of the human P2X7 receptor". Receptors & Channels. 5 (6): 347–54. PMID9826911.
^ abFaria RX, Freitas HR, Reis RA (June 2017). "P2X7 receptor large pore signaling in avian Müller glial cells". Journal of Bioenergetics and Biomembranes. 49 (3): 215–229. doi:10.1007/s10863-017-9717-9. PMID28573491. S2CID4122579.
^Collo G, Neidhart S, Kawashima E, Kosco-Vilbois M, North RA, Buell G (September 1997). "Tissue distribution of the P2X7 receptor". Neuropharmacology. 36 (9): 1277–83. doi:10.1016/S0028-3908(97)00140-8. PMID9364482. S2CID21491471.
^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. doi:10.1023/A:1004017714702. PMID10943851. S2CID40282870.
^Ishii K, Kaneda M, Li H, Rockland KS, Hashikawa T (May 2003). "Neuron-specific distribution of P2X7 purinergic receptors in the monkey retina". The Journal of Comparative Neurology. 459 (3): 267–77. doi:10.1002/cne.10608. PMID12655509. S2CID9692745.
^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. doi:10.1007/s12035-019-1537-y. PMID30838518. S2CID71143662.
^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. doi:10.1016/j.bbrc.2012.01.156. PMID22349510.
^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. doi:10.1016/j.neulet.2011.08.058. PMID21924325. S2CID32284927.
^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. doi:10.1046/j.1471-4159.2000.0750965.x. PMID10936177. S2CID84445342.
Gartland A, Buckley KA, Hipskind RA, Bowler WB, Gallagher JA (2003). "P2 receptors in bone--modulation of osteoclast formation and activity via P2X7 activation". Critical Reviews in Eukaryotic Gene Expression. 13 (2–4): 237–42. doi:10.1615/CritRevEukaryotGeneExpr.v13.i24.150. PMID14696970.
Gartland A, Buckley KA, Bowler WB, Gallagher JA (October 2003). "Blockade of the pore-forming P2X7 receptor inhibits formation of multinucleated human osteoclasts in vitro". Calcified Tissue International. 73 (4): 361–9. doi:10.1007/s00223-002-2098-y. PMID12874700. S2CID23793221.
Bowler WB, Buckley KA, Gartland A, Hipskind RA, Bilbe G, Gallagher JA (May 2001). "Extracellular nucleotide signaling: a mechanism for integrating local and systemic responses in the activation of bone remodeling". Bone. 28 (5): 507–12. doi:10.1016/S8756-3282(01)00430-6. PMID11344050.
Gartland A, Buckley KA, Hipskind RA, Perry MJ, Tobias JH, Buell G, et al. (2003). "Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice". Critical Reviews in Eukaryotic Gene Expression. 13 (2–4): 243–53. doi:10.1615/CritRevEukaryotGeneExpr.v13.i24.160. PMID14696971.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Wiley JS, Dao-Ung LP, Gu BJ, Sluyter R, Shemon AN, Li C, et al. (March 2002). "A loss-of-function polymorphic mutation in the cytolytic P2X7 receptor gene and chronic lymphocytic leukaemia: a molecular study". Lancet. 359 (9312): 1114–9. doi:10.1016/S0140-6736(02)08156-4. PMID11943260. S2CID6019286.
Greig AV, Linge C, Terenghi G, McGrouther DA, Burnstock G (June 2003). "Purinergic receptors are part of a functional signaling system for proliferation and differentiation of human epidermal keratinocytes". The Journal of Investigative Dermatology. 120 (6): 1007–15. doi:10.1046/j.1523-1747.2003.12261.x. PMID12787128.
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