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Molecular Pain
Published in: Molecular Pain 1/2014

Open Access 01-12-2014 | Research

Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain

Authors: Daniel Ursu, Philip Ebert, Emily Langron, Cara Ruble, Leanne Munsie, Wei Zou, Bonnie Fijal, Yue-Wei Qian, Terry A McNearney, Adrian Mogg, Olivera Grubisha, Kalpana Merchant, Emanuele Sher

Published in: Molecular Pain | Issue 1/2014

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Abstract

Background

Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis.

Results

The functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores.

Conclusions

Our present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population.
Appendix
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Literature
1.
2.
Dell’Antonio G, Quattrini A, Dal CE, Fulgenzi A, Ferrero ME: Antinociceptive effect of a new P(2Z)/P2X7 antagonist, oxidized ATP, in arthritic rats. Neurosci Lett 2002, 327: 87–90.PubMedCrossRef
3.
Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN: Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 2005, 114: 386–396.PubMedCrossRef
4.
Honore P, Donnelly-Roberts D, Namovic MT, Hsieh G, Zhu CZ, Mikusa JP, Hernandez G, Zhong C, Gauvin DM, Chandran P, Harris R, Medrano AP, Carroll W, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF: A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. J Pharmacol Exp Ther 2006, 319: 1376–1385.PubMedCrossRef
5.
Takenouchi T, Sekiyama K, Sekigawa A, Fujita M, Waragai M, Sugama S, Iwamaru Y, Kitani H, Hashimoto M: P2X7 receptor signaling pathway as a therapeutic target for neurodegenerative diseases. Arch Immunol Ther Exp (Warsz) 2010, 58: 91–96.CrossRef
6.
Murphy N, Cowley TR, Richardson JC, Virley D, Upton N, Walter D, Lynch MA: The neuroprotective effect of a specific P2X(7) receptor antagonist derives from its ability to inhibit assembly of the NLRP3 inflammasome in glial cells. Brain Pathol 2012, 22: 295–306.PubMedCrossRef
7.
8.
Surprenant A, Buell G, North RA: P2X receptors bring new structure to ligand-gated ion channels. Trends Neurosci 1995, 18: 224–229.PubMedCrossRef
9.
10.
11.
Pelegrin P, Surprenant A: Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 2006, 25: 5071–5082.PubMedCentralPubMedCrossRef
12.
Browne LE, Compan V, Bragg L, North RA: P2X7 receptor channels allow direct permeation of nanometer-sized dyes. J Neurosci 2013, 33: 3557–3566.PubMedCrossRef
13.
Di VF: Liaisons dangereuses: P2X(7) and the inflammasome. Trends Pharmacol Sci 2007, 28: 465–472.CrossRef
14.
Surprenant A, Rassendren F, Kawashima E, North RA, Buell G: The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 1996, 272: 735–738.PubMedCrossRef
15.
Ferrari D, Chiozzi P, Falzoni S, Dal SM, Melchiorri L, Baricordi OR, Di VF: Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J Immunol 1997, 159: 1451–1458.PubMed
16.
MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A: Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity 2001, 15: 825–835.PubMedCrossRef
17.
Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, Griffiths RJ, Gabel CA: Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 2001, 276: 125–132.PubMedCrossRef
18.
Labasi JM, Petrushova N, Donovan C, McCurdy S, Lira P, Payette MM, Brissette W, Wicks JR, Audoly L, Gabel CA: Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J Immunol 2002, 168: 6436–6445.PubMedCrossRef
19.
Al-Shukaili A, Al-Kaabi J, Hassan B: A comparative study of interleukin-1beta production and p2x7 expression after ATP stimulation by peripheral blood mononuclear cells isolated from rheumatoid arthritis patients and normal healthy controls. Inflammation 2008, 31: 84–90.PubMedCrossRef
20.
Barbera-Cremades M, Baroja-Mazo A, Gomez AI, Machado F, Di VF, Pelegrin P: P2X7 receptor-stimulation causes fever via PGE2 and IL-1beta release. FASEB J 2012, 26: 2951–2962.PubMedCrossRef
21.
Sorge RE, Trang T, Dorfman R, Smith SB, Beggs S, Ritchie J, Austin JS, Zaykin DV, Vander MH, Costigan M, Herbert TA, Yarkoni-Abitbul M, Tichauer D, Livneh J, Gershon E, Zheng M, Tan K, John SL, Slade GD, Jordan J, Woolf CJ, Peltz G, Maixner W, Diatchenko L, Seltzer Z, Salter MW, Mogil JS: Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med 2012, 18: 595–599.PubMedCentralPubMedCrossRef
22.
Cabrini G, Falzoni S, Forchap SL, Pellegatti P, Balboni A, Agostini P, Cuneo A, Castoldi G, Baricordi OR, Di VF: A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes. J Immunol 2005, 175: 82–89.PubMedCrossRef
23.
Stokes L, Fuller SJ, Sluyter R, Skarratt KK, Gu BJ, Wiley JS: Two haplotypes of the P2X(7) receptor containing the Ala-348 to Thr polymorphism exhibit a gain-of-function effect and enhanced interleukin-1beta secretion. FASEB J 2010, 24: 2916–2927.PubMedCrossRef
24.
Gu BJ, Zhang W, Worthington RA, Sluyter R, Dao-Ung P, Petrou S, Barden JA, Wiley JS: A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. J Biol Chem 2001, 276: 11135–11142.PubMedCrossRef
25.
Sun C, Chu J, Singh S, Salter RD: Identification and characterization of a novel variant of the human P2X(7) receptor resulting in gain of function. Purinergic Signal 2010, 6: 31–45.PubMedCentralPubMedCrossRef
26.
Roger S, Mei ZZ, Baldwin JM, Dong L, Bradley H, Baldwin SA, Surprenant A, Jiang LH: Single nucleotide polymorphisms that were identified in affective mood disorders affect ATP-activated P2X7 receptor functions. J Psychiatr Res 2010, 44: 347–355.PubMedCrossRef
27.
Bradley HJ, Baldwin JM, Goli GR, Johnson B, Zou J, Sivaprasadarao A, Baldwin SA, Jiang LH: Residues 155 and 348 contribute to the determination of P2X7 receptor function via distinct mechanisms revealed by single-nucleotide polymorphisms. J Biol Chem 2011, 286: 8176–8187.PubMedCentralPubMedCrossRef
28.
Wesselius A, Bours MJ, Arts IC, Theunisz EH, Geusens P, Dagnelie PC: The P2X(7) loss-of-function Glu496Ala polymorphism affects ex vivo cytokine release and protects against the cytotoxic effects of high ATP-levels. BMC Immunol 2012, 13: 64.PubMedCentralPubMedCrossRef
29.
Donnelly-Roberts DL, Namovic MT, Surber B, Vaidyanathan SX, Perez-Medrano A, Wang Y, Carroll WA, Jarvis MF: [3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selective antagonist radioligand for P2X7 receptors. Neuropharmacology 2009, 56: 223–229.PubMedCrossRef
30.
Alcaraz L, Baxter A, Bent J, Bowers K, Braddock M, Cladingboel D, Donald D, Fagura M, Furber M, Laurent C, Lawson M, Mortimore M, McCormick M, Roberts N, Robertson M: Novel P2X7 receptor antagonists. Bioorg Med Chem Lett 2003, 13: 4043–4046.PubMedCrossRef
31.
Tanenberg RJ, Irving GA, Risser RC, Ahl J, Robinson MJ, Skljarevski V, Malcolm SK: Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison. Mayo Clin Proc 2011, 86: 615–626.PubMedCentralPubMedCrossRef
32.
McHugh SM, Roman S, Davis B, Koch A, Pickett AM, Richardson JC, Miller SR, Wetten S, Cox CJ, Karpe F, Todd JA, Bullmore ET: Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X(7) receptor antagonist: a prospective genotyping approach. Br J Clin Pharmacol 2012, 74: 376–380.PubMedCentralPubMedCrossRef
33.
Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL III: Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009, 10: 447–485.PubMedCentralPubMedCrossRef
34.
35.
Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV, Lariviere WR, Groce MK, Wallace MR, Kaplan L, Staud R, Ness TJ, Glover TL, Stankova M, Mayorov A, Hruby VJ, Grisel JE, Fillingim RB: The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci U S A 2003, 100: 4867–4872.PubMedCentralPubMedCrossRef
36.
Fillingim RB, Kaplan L, Staud R, Ness TJ, Glover TL, Campbell CM, Mogil JS, Wallace MR: The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. J Pain 2005, 6: 159–167.PubMedCrossRef
37.
Gartland A, Skarratt KK, Hocking LJ, Parsons C, Stokes L, Jorgensen NR, Fraser WD, Reid DM, Gallagher JA, Wiley JS: Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women. Eur J Hum Genet 2012, 20: 559–564.PubMedCentralPubMedCrossRef
38.
Wesselius A, Bours MJ, Henriksen Z, Syberg S, Petersen S, Schwarz P, Jorgensen NR, Van HS, Dagnelie PC: Association of P2X7 receptor polymorphisms with bone mineral density and osteoporosis risk in a cohort of Dutch fracture patients. Osteoporos Int 2013, 24: 1235–1246.PubMedCentralPubMedCrossRef
39.
Ohlendorff SD, Tofteng CL, Jensen JE, Petersen S, Civitelli R, Fenger M, Abrahamsen B, Hermann AP, Eiken P, Jorgensen NR: Single nucleotide polymorphisms in the P2X7 gene are associated to fracture risk and to effect of estrogen treatment. Pharmacogenet Genomics 2007, 17: 555–567.PubMedCrossRef
40.
Jørgensen NR, Husted LB, Skarratt KK, Stokes L, Tofteng CL, Kvist T, Jensen JE, Eiken P, Brixen K, Fuller S, Clifton-Bligh R, Gartland A, Schwarz P, Langdahl BL, Wiley JS: Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures. Eur J Hum Genet 2012, 20: 675–681.PubMedCentralPubMedCrossRef
41.
Novak I, Jans IM, Wohlfahrt L: Effect of P2X(7) receptor knockout on exocrine secretion of pancreas, salivary glands and lacrimal glands. J Physiol 2010, 588: 3615–3627.PubMedCentralPubMedCrossRef
42.
Ke HZ, Qi H, Weidema AF, Zhang Q, Panupinthu N, Crawford DT, Grasser WA, Paralkar VM, Li M, Audoly LP, Gabel CA, Jee WS, Dixon SJ, Sims SM, Thompson DD: Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption. Mol Endocrinol 2003, 17: 1356–1367.PubMedCrossRef
43.
Cervetto C, Frattaroli D, Maura G, Marcoli M: Motor neuron dysfunction in a mouse model of ALS: gender-dependent effect of P2X7 antagonism. Toxicology 2013, 311: 69–77.PubMedCrossRef
44.
Portales H, Goubet N, Sirotkin S, Duval E, Mermet A, Albouy PA, Pileni MP: Crystallinity segregation upon selective self-assembling of gold colloidal single nanocrystals. Nano Lett 2012, 12: 5292–5298.PubMedCrossRef
45.
Backonja MM, Coe CL, Muller DA, Schell K: Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients. J Neuroimmunol 2008, 195: 157–163.PubMedCrossRef
46.
Michel AD, Chessell IP, Humphrey PP: Ionic effects on human recombinant P2X7 receptor function. Naunyn Schmiedebergs Arch Pharmacol 1999, 359: 102–109.PubMedCrossRef
47.
Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA: A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994, 17: 1281–1289.PubMedCrossRef
Metadata
Title
Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain
Authors
Daniel Ursu
Philip Ebert
Emily Langron
Cara Ruble
Leanne Munsie
Wei Zou
Bonnie Fijal
Yue-Wei Qian
Terry A McNearney
Adrian Mogg
Olivera Grubisha
Kalpana Merchant
Emanuele Sher
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2014
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-10-37

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