P2X Receptor-Dependent Modulation: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Barbora Salcman.

P2X receptors (P2XRs) are membrane ligand-gated ion channels and are members of the purinergic receptor family. Of the seven P2XR family members, only four of them (P2X1, P2X4, P2X6 and P2X7) have been shown to be expressed in MCs, with each of them playing an important role in regulating MC activities, such as Ca+ influx and degranulation. P2XRs are also present in neurons and glial cells, where their engagement may affect the development of neuroinflammatory pathologies such as the Alzheimer’s disease (AD), Parkinson’s disease (PD) and Multiple sclerosis (MS).

  • mast cells
  • microglia
  • astrocytes
  • oligodendrocytes
  • P2X receptors

1. Introduction

Mast cells (MCs) are immune cells that form part of the innate branch of the immune system. Since MCs express a broad spectrum of high affinity receptors (e.g., high-affinity IgE receptor (FcɛRI), Fc-gamma receptor (FcγR), complement receptors and purinergic receptors), they rapidly respond to a variety of environmental and immune stimuli, resulting in the release of pre-formed mediators such as histamine and then later the production of newly synthesized cytokines, chemokines, growth factors, proteases, and lipid mediators [1,2,3][1][2][3].

MCs are of dual hematopoietic origin. In mice, a first wave of MCs originates during embryonic development from yolk-sac progenitors followed by a second wave of bone marrow-derived MCs in adulthood. This duality in the origin of MCs may influence the cell phenotype and function in various tissues [4,5][4][5]. After leaving the bone marrow, MC committed progenitors circulate in the bloodstream and mature in peripheral tissues under the influence of a cocktail of growth factors that include the stem cell factor [6,7][6][7].

Human MCs are found in low numbers in the hypothalamus, leptomeninges, area postrema, and the dura matter of the spinal cord [8]. Nearly 97% of all MCs found in the brain are positioned in the abluminal side of the brain blood vessels, which allows them to communicate with neurons, glial cells (such as astrocytes and microglia) and endothelial cells [8,9][8][9]. In the human brain, MC density was found to be less than <5 MCs in 5 μm thick tissue sections in meninges and perivascular area. However, during viral, bacterial and parasitic infections, MC numbers were observed to be higher, at around 11–20 cells per 5 μm thick tissue section in meninges and around 5–20 in perivascular area [10]. In the healthy brain the predominant MC phenotype is tryptase+ chymase+ and their overall numbers can be affected by trauma and/or stress, whilst their activation could potentially influence social behaviour [9,10,11,12][9][10][11][12]. The number of MCs in the brain can be sex-dependent, especially in young mice pups, where the total number of MCs in the preoptic area is nearly two times higher for males than females, potentially contributing to the gender bias in human neuropathology for diseases such as autism spectrum disorder (ASD) or schizophrenia [13,14][13][14]. MC numbers are also age-dependent, with MCs being most abundant in brains of individuals under 19 years old, a pattern probably related to the age involution [8,15,16][8][15][16].

2. Expression of P2XRs and the Role of ATP and P2XR Activation in Neuroinflammation

2.1. ATP Release during Inflammation and Brain Pathology

In the CNS, extracellular ATP acts as a fast-excitatory neurotransmitter and an important mediator for neuron-glial, glial-glial, and neuron-neuron communication [62,63][17][18]. In a healthy tissue, ATP is found extracellularly at negligible concentrations, with neurons and glial cells carrying millimolar concentrations of ATP intracellularly [64][19]. This is released by Panx1 and Connexin channels, through vesicular transport or through membrane stress/damage [65][20]. For example, during inflammation, necrotic cells set free up to hundreds of µmol/L of ATP [66][21]. Increased concentrations of ATP have been detected in brain pathologies upon trauma, ischemia, epilepsy, PD or MS [67,68,69][22][23][24].

2.2. Expression of P2XRs and The Role of ATP and P2XR Activation in Glial Cells

Extracellular ATP is the sole activator of all P2XR family members and undergoes a rapid enzymatic degradation into adenosine diphosphate (ADP) upon extracellular release, which is then further degraded into adenosine monophosphate (AMP) and adenosine [70,71][25][26]. P2XR engagement by ATP activates Na+ and Ca2+ influx, and K+ efflux, resulting in the plasma membrane depolarisation and reorganization, release of cytokines (such as IL-6, IL-8 and TNF-α) and caspase activation [72,73][27][28]. The seven P2XRs exhibit different affinities for ATP and exist as homomeric or heteromeric receptors, with homomeric P2X5 and P2X6 potentially not being functional in humans. For P2X6 in particular heteromerization appears to be necessary for a correct folding and assembly [74,75,76][29][30][31].
Together with the P2XRs, eight different P2YRs belong to the purinergic receptor family. P2YRs are G-protein coupling receptors expressed and functional on MCs and glial cells and involved in AD or epilepsy disease pathogenesis [77,78,79,80][32][33][34][35]. However, since the P2YRs are activated by multiple mediators, such as ATP, ADP, UTP, UDP and UDP-glucose [81][36] and since this review only examines the unique role of ATP in linking glial and MC activities, these receptors will not be discussed further.

2.3. P2XR Expression in Astrocytes

In astrocytes, P2X1 exists as a homomeric, or as a P2X1/P2X5 heteromeric receptor, the latter having unique properties compared to its homomeric counterpart. For example, the P2X1/P2X5 heteromeric receptor in astrocytes has a higher sensitivity to ATP with no desensitization response compared to the homomeric P2X1 [82,83][37][38]. However, P2X1/P2X5 expression is age-dependent, with a lack of heterodimers in 6 month old mice [22][39]. It is therefore unlikely that this receptor has an impact on astrocytes activities in adult mice.
P2X2 activation in astrocytes was found to regulate GABAergic transmission and ASD like behaviour in C57BL/6J mice carrying a knockout of the type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2) gene, as mutations in this gene are associated with ASD [84][40]. Activation of the P2X2 also led to an increase in mRNA expression of leukaemia inhibitory factor (LIF), a cytokine inhibiting cell differentiation, in astrocytes isolated from neonatal C57BL/6J mice. Thus, this contributing to the efficacy of electroconvulsive therapy in psychiatric disorders [85][41].
Expression of P2X3 was reported in astrocytes in Sprague-Dawley rats [86][42] and in primary astrocytes cultures obtained from rats cerebral cortex [87][43], with receptor activation modulating craniofacial neuropathic pain [88][44].
Regarding P2X4, there is still limited evidence of its expression in astrocytes. This was demonstrated by RT-PCR and immunohistochemistry in rat cells [89,90][45][46]. However, studies performed in GFAP promoter-controlled EGFP-expressing (GFAP/EGFP) transgenic mice and in vitro using hippocampal slices from transgenic GFAP/EGFP mice and Wistar rats did not detect any P2X4-mediated ATP-induced current [82,91][37][47].
Rat cortical astrocytes [87][43] and human astrocytes isolated from foetal cortex express P2X5 [92][48]. However, knowledge about the receptor functionality is restricted to the P2X1/P2X5 heterodimers [80][35].
The presence of P2X6 in astrocytes remains controversial, as RT-PCR and western blotting of primary astrocytes from rats cerebral cortex didn’t show any expression [87][43], whilst P2X6 expression was detected using qPCR in human astrocytes from foetal cortex [92][48] and in astrocytes end-feet derived from Sprague-Dawley rats [93][49].
P2X7 activation was shown to attenuate LPS-induced release of TNF-α in primary cultures of rat cortical astrocytes [94][50]. In contrast, stimulation of P2X7 in mouse astrocyte cultures resulted in the secretion of various transmitter molecules, such as glutamate or GABA [95][51], and of a MAP kinase-controlled secretion of CCL2 in the Sprague-Dawley rat astrocytes [96][52]. In the hippocampus of C57BL/6J mice, P2X7 activation with extracellular ATP resulted in the release of neurotransmitters from astrocytes, leading to the stimulation of surrounding neurons [97][53]. In human foetal astrocyte cultures, regulation of P2X7 was induced by IL-1β [98][54] and its expression was observed in astrocytes from post-mortem brain tissues sections in AD patients [99][55]. In SOD1 mice astrocytes, P2X7 activation contributed to their toxicity towards motor neurons [100][56].

2.4. P2XR Expression in Microglia

In both mouse and human microglia, P2X4 and P2X7 are highly expressed [101][57], while evidence for the expression of P2X1, P2X2, P2X3 and P2X6 remains controversial. In this regard, microglia cultures obtained from Sprague-Dawley rats and BV-2 (immortalized murine microglia) cells showed P2X1 expression [102,103][58][59], whilst C57BL/6J and SOD1 mice microglia cells displayed very low or no expression [104,105][60][61]. Xiang & Burnstock [106][62] showed P2X1 expression in Wistar rats microglia only at late stages of embryonic development and until day 30 of postnatal development, suggesting that the expression of P2X1 in animal models might be species and age dependent. In human microglia, voltage-clamp electrophysiology performed after ATP stimulation in two donors showed no evidence of rapid desensitising inward current expected from P2X1 and P2X3 engagement [107][63]. RNA sequencing studies by Chiu et al. [108][64] and Solga et al. [109][65] in microglia from SOD1 and C57BL/6 mice, detected either none or extremely low expression levels of P2X1, P2X2, P2X3, P2X5 and P2X6, respectively. On the contrary, western blot analysis of N9 murine microglial cell line showed the presence of P2X1, P2X2, P2X3 and P2X6 [110][66]. Thus, discrepancies in P2X1, P2X2, P2X3 and P2X6 expression were found not only between species but also in similar murine systems.
P2X4 plays a major role in the regulation of neuronal and glial functions, as peripheral damage induces an upregulation of P2X4 in microglia and affects the inflammatory response [111][67]. It appears that P2X4 in rat cultured microglia is predominantly stored intracellularly while membrane expression is rapidly upregulated through C-C chemokine receptor type (CCR) 2-mediated activation upon CCL2 or CCL12 ligand binding [112][68]. Stimulation of P2X4 in mice microglia leads to maintained mechanical hypersensitivity after nerve injury, through the release of brain-derived neurotrophic factor [113][69], which is a crucial signalling mediator between microglia and neurons [114][70]. Deletion of P2X4 in P2X4−/− KO mice resulted in the absence of mechanical hypersensitivity after peripheral nerve lesion [113][69]. In a mouse model of experimental autoimmune encephalomyelitis (EAE), P2X4 was shown to be a modulator of microglia polarization and its increase in expression to be a marker of the neuroinflammatory response [115][71]. Furthermore, P2X4 was also suggested to contribute to the activation and migration of Lewis rat microglia into the site of a formalin-induced injury [116][72].
Activation of the P2X7 in mice microglia results in the activation of the inflammasome, release of TNF-α, CCL2, IL-6, IL-1β, and IL-18, and increased cell death [117,118][73][74]. In healthy human donors, microglia isolated from the cortex expressed functional P2X7, but no release of IL-1β or IL-18 was observed upon LPS priming and subsequent ATP stimulation. The authors hypothesized that the cultured cells switched from a M1 inflammatory phenotype to an anti-inflammatory M2 phenotype in the presence of serum contained in the culture medium, therefore possibly shifting the nature of the microglia behaviour [107][63].
P2X7 activity in microglia has been linked to several neuroinflammatory diseases. In a mouse model of AD, upregulation of P2X7 expression was observed in microglia in proximity to Aβ peptide aggregates, and this expression was further elevated in the later stages of Aβ pathology. The same results were then observed in AD patients, suggesting an importance of P2X7 in AD pathology [23,99,119][75][55][76]. P2X7 activation in microglia has also been linked to MS, stress, depression, and PD in Sprague-Dawley rats, Wistar rats and C57BL/6J mice models [24,25,120,121][77][78][79][80]. Upregulation of P2X7 expression in microglia was observed in SOD1 mice [122][81] and receptor activation was found to modulate autophagic flux, a homeostatic mechanism involved in degradation of damaged organelles and protein aggregates, whose abnormalities were reported in ASL [123][82]. Inhibition of P2X7 using brilliant blue G showed prolonged survival in female SOD1 mice [124][83], while administration of JNJ-47965567 P2X7 inhibitor in the same model did not alter ALS progression [125][84].

2.5. P2XR Expression in Oligodendrocytes

Expression of P2X1, P2X2 and P2X3 was observed in oligodendrocytes progenitor cells isolated from postnatal 1 day Wistar rats [126][85] and in human stem cell-derived oligodendrocytes progenitor cells [127][86], while was absent in mouse mature and progenitor oligodendrocytes [128][87].
P2X4 expression in oligodendrocytes was confirmed by western blot analysis, qPCR and RNA sequencing in mice, rats and human progenitor oligodendrocytes [126,127,128][85][86][87]. However, Zabala et al. [115][71] were unable to link receptor expression to functionality in these cells. P2X5 and P2X6 were not found in oligodendrocytes lineage cells [129][88].
In contrast to other P2XRs, the functionality of P2X7 in oligodendrocytes has been demonstrated by Matute et al. [130][89] where a continuous activation of P2X7 led to the oligodendrocytes’ death, due to the P2X7-mediated Ca2+ toxicity. Furthermore, an increase in P2X7 expression in oligodendrocytes was found in samples from patients with MS, in a mouse model in post-episodes of status epilepticus and during epilepsy [131][90], and in rat model of ischemic damage [132][91].
Overall, P2XR activities in glial cells are yet unclear, with the exception of P2X7, which engagement initiates the release of mediators whose nature differs between species [101,133][57][92].

2.6. Expression of P2XRs and The Role of ATP and P2XR Activation in MCs

In MCs, expression of P2X1, P2X4 and P2X7 has been confirmed by RT-PCR analysis in LAD2 cells and human lung MCs, and by proteomics analysis in human and mouse primary connective tissue MCs [19,134][93][94]. P2X6 expression has also been observed in LAD2 and human lung MCs, however its functionality has not been demonstrated yet [19,135][93][95].
The MC homomeric P2X1 binds ATP with high affinity, with only 1 μM needed to activate P2X1 in LAD2 cells [19][93]. Study by Wareham & Seward [20][96] observed that the engagement of the P2X1 triggers a fast and transient calcium influx and a prolonged exposure to even low ATP concentrations may lead to its desensitisation. Even though it was concluded that P2X1 activation in LAD2 cells does not trigger degranulation, it was not investigated further if the activation might lead to a release of specific mediators.
Like the P2X1, P2X4 activation leads to a calcium influx into MCs without inducing degranulation. However, P2X4 activation with an ATP concentration of less than 300 μM significantly increased degranulation mediated by high-affinity IgE receptor or by G-coupled prostaglandin EP3 receptor stimulation in bone marrow-derived MCs (BMMCs) from C57BL/6 mice [21,136][97][98]. P2X4 stimulation by ATP was also shown to enhance antigen-induced phosphorylation of Syk and PLCγ signalling pathways in mice BMMCs, independent of the P2X4-mediated calcium influx [137][99]. Inhibition of P2X4, by the potent and selective benzodiazepine derivative 5-BDBD, in human lung MCs diminished release of cysteinyl leukotrienes [135][95].
To date, P2X7 is the only P2XR demonstrated to induce MC degranulation. Activation of P2X7 triggers degranulation of meningeal MCs derived from C57BL/6 mice and human LAD2 cells [20[96][100],138], resulting in the immediate release of many pre-stored inflammatory mediators (such as histamine, tryptase, chymase, IL-6, IL-1β, and CCL2), with others, such as IL-5, CCL3 and eicosanoids, being newly synthesised over time [139,140][101][102]. Furthermore Shimokawa et al. [141][103] reported that P2X7 activation by ATP induced the secretion of IL-33 in mouse BMMCs.
In contrast to glial cells, P2X1, P2X4, P2X6 and P2X7 expression has been observed in vivo and in vitro in murine and human MCs, with P2X7 detected in brain resident MCs [19,134,138][93][94][100].

2.7. Expression of P2XRs: Public Gene Expression Databases

The availability of public datasets such as the iFANTOM and ImmGen consortiums now provide a useful tool to glean additional information on the expression of P2XRs in MCs and glial cells. P2X1, P2X4 and P2X7 are mostly expressed in the peritoneal cavity while P2X2, P2X3, P2X5 and P2X6 expression is constitutive and shared between organs and tissues. It should be noted, that P2XR expression is lower in MCs and glial cells compared to other cell types, except for P2X1, which exhibits the highest expression in skin MCs.

References

  1. Mukai, K.; Tsai, M.; Saito, H.; Galli, S.J. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol. Rev. 2018, 282, 121–150.
  2. Olivera, A.; Beaven, M.A.; Metcalfe, D.D. Mast cells signal their importance in health and disease. J. Allergy Clin. Immunol. 2018, 142, 381–393.
  3. Galli, S.J.; Gaudenzio, N.; Tsai, M. Mast Cells in Inflammation and Disease: Recent Progress and Ongoing Concerns. Annu. Rev. Immunol. 2020, 38, 49–77.
  4. Gentek, R.; Ghigo, C.; Hoeffel, G.; Bulle, M.J.; Msallam, R.; Gautier, G.; Launay, P.; Chen, J.; Ginhoux, F.; Bajénoff, M. Hemogenic Endothelial Fate Mapping Reveals Dual Developmental Origin of Mast Cells. Immunity 2018, 48, 1160.e5–1171.e5.
  5. Li, Z.; Liu, S.; Xu, J.; Zhang, X.; Han, D.; Liu, J.; Xia, M.; Yi, L.; Shen, Q.; Xu, S.; et al. Adult Connective Tissue-Resident Mast Cells Originate from Late Erythro-Myeloid Progenitors. Immunity 2018, 49, 640.e5–653.e5.
  6. Dahlin, J.S.; Ungerstedt, J.S.; Grootens, J.; Sander, B.; Gülen, T.; Hägglund, H.; Nilsson, G. Detection of circulating mast cells in advanced systemic mastocytosis. Leukemia 2016, 30, 1953–1956.
  7. Méndez-Enríquez, E.; Hallgren, J. Mast Cells and Their Progenitors in Allergic Asthma. Front. Immunol. 2019, 10, 821.
  8. Traina, G. Mast Cells in Gut and Brain and Their Potential Role as an Emerging Therapeutic Target for Neural Diseases. Front. Cell Neurosci. 2019, 13, 345.
  9. Hendriksen, E.; van Bergeijk, D.; Oosting, R.S.; Redegeld, F.A. Mast cells in neuroinflammation and brain disorders. Neurosci. Biobehav. Rev. 2017, 79, 119–133.
  10. Maślińska, D.; Laure-Kamionowska, M.; Gujski, M.; Ciurzynska, G.; Wojtecka-Lukasik, E. Post-infectional distribution and phenotype of mast cells penetrating human brains. Inflamm. Res. 2005, 54 (Suppl. S1), S15–S16.
  11. Joshi, A.; Page, C.E.; Damante, M.; Dye, C.N.; Haim, A.; Leuner, B.; Lenz, K.M. Sex differences in the effects of early life stress exposure on mast cells in the developing rat brain. Horm. Behav. 2019, 113, 76–84.
  12. Tanioka, D.; Chikahisa, S.; Shimizu, N.; Shiuchi, T.; Sakai, N.; Nishino, S.; Séi, H. Intracranial mast cells contribute to the control of social behavior in male mice. Behav. Brain Res. 2021, 403, 113143.
  13. Lenz, K.M.; Pickett, L.A.; Wright, C.L.; Davis, K.T.; Joshi, A.; McCarthy, M.M. Mast Cells in the Developing Brain Determine Adult Sexual Behavior. J. Neurosci. 2018, 38, 8044–8059.
  14. McCarthy, M.M.; Nugent, B.M.; Lenz, K.M. Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nat. Rev. Neurosci. 2017, 18, 471–484.
  15. Silver, R.; Curley, J.P. Mast cells on the mind: New insights and opportunities. Trends Neurosci. 2013, 36, 513–521.
  16. Turygin, V.V.; Babik, T.M.; Boyakov, A.A. Characteristics of mast cells in the choroid plexus of the ventricles of the human brain in aging. Neurosci. Behav. Physiol. 2005, 35, 909–911.
  17. Lalo, U.; Verkhratsky, A.; Pankratov, Y. Ionotropic ATP receptors in neuronal-glial communication. Semin. Cell Dev. Biol. 2011, 22, 220–228.
  18. Cisneros-Mejorado, A.; Pérez-Samartín, A.; Gottlieb, M.; Matute, C. ATP signaling in brain: Release, excitotoxicity and potential therapeutic targets. Cell Mol. Neurobiol. 2015, 35, 1–6.
  19. Abbracchio, M.P.; Burnstock, G.; Verkhratsky, A.; Zimmermann, H. Purinergic signalling in the nervous system: An overview. Trends Neurosci. 2009, 32, 19–29.
  20. Merighi, S.; Poloni, T.E.; Terrazzan, A.; Moretti, E.; Gessi, S.; Ferrari, D. Alzheimer and Purinergic Signaling: Just a Matter of Inflammation? Cells 2021, 10, 1267.
  21. Di Virgilio, F.; Sarti, A.C.; Coutinho-Silva, R. Purinergic signaling, DAMPs, and inflammation. Am. J. Physiol. Cell Physiol. 2020, 318, C832–c835.
  22. Rodrigues, R.J.; Tomé, A.R.; Cunha, R.A. ATP as a multi-target danger signal in the brain. Front. Neurosci. 2015, 9, 148.
  23. Atif, M.; Alsrhani, A.; Naz, F.; Imran, M.; Imran, M.; Ullah, M.I.; Alameen, A.A.M.; Gondal, T.A.; Raza, Q. Targeting Adenosine Receptors in Neurological Diseases. Cell Reprogram. 2021, 23, 57–72.
  24. Dosch, M.; Gerber, J.; Jebbawi, F.; Beldi, G. Mechanisms of ATP Release by Inflammatory Cells. Int. J. Mol. Sci. 2018, 19, 1222.
  25. Dou, L.; Chen, Y.F.; Cowan, P.J.; Chen, X.P. Extracellular ATP signaling and clinical relevance. Clin. Immunol. 2018, 188, 67–73.
  26. Burnstock, G. Introduction to Purinergic Signalling in the Brain. In Glioma Signaling. Advances in Experimental Medicine and Biology; Barańska, J., Ed.; Springer: Cham, Switzerland, 2020.
  27. Di Virgilio, F.; Dal Ben, D.; Sarti, A.C.; Giuliani, A.L.; Falzoni, S. The P2X7 Receptor in Infection and Inflammation. Immunity 2017, 47, 15–31.
  28. Kopp, R.; Krautloher, A.; Ramírez-Fernández, A.; Nicke, A. P2X7 Interactions and Signaling—Making Head or Tail of It. Front. Mol. Neurosci. 2019, 12, 183.
  29. Saul, A.; Hausmann, R.; Kless, A.; Nicke, A. Heteromeric assembly of P2X subunits. Front. Cell Neurosci. 2013, 7, 250.
  30. Hou, Z.; Cao, J. Comparative study of the P2X gene family in animals and plants. Purinergic Signal. 2016, 12, 269–281.
  31. Jacobson, K.A.; Müller, C.E. Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology 2016, 104, 31–49.
  32. Kong, Q.; Peterson, T.S.; Baker, O.; Stanley, E.; Camden, J.; Seye, C.I.; Erb, L.; Simonyi, A.; Wood, W.G.; Sun, G.Y.; et al. Interleukin-1beta enhances nucleotide-induced and alpha-secretase-dependent amyloid precursor protein processing in rat primary cortical neurons via up-regulation of the P2Y(2) receptor. J. Neurochem. 2009, 109, 1300–1310.
  33. Álvarez-Ferradas, C.; Morales, J.C.; Wellmann, M.; Nualart, F.; Roncagliolo, M.; Fuenzalida, M.; Bonansco, C. Enhanced astroglial Ca2+ signaling increases excitatory synaptic strength in the epileptic brain. Glia 2015, 63, 1507–1521.
  34. Alves, M.; Beamer, E.; Engel, T. The Metabotropic Purinergic P2Y Receptor Family as Novel Drug Target in Epilepsy. Front. Pharmacol. 2018, 9, 193.
  35. Agostinho, P.; Madeira, D.; Dias, L.; Simões, A.P.; Cunha, R.A.; Canas, P.M. Purinergic signaling orchestrating neuron-glia communication. Pharmacol. Res. 2020, 162, 105253.
  36. Gao, Z.G.; Jacobson, K.A. Purinergic Signaling in Mast Cell Degranulation and Asthma. Front. Pharmacol. 2017, 8, 947.
  37. Lalo, U.; Pankratov, Y.; Wichert, S.P.; Rossner, M.J.; North, R.A.; Kirchhoff, F.; Verkhratsky, A. P2X1 and P2X5 subunits form the functional P2X receptor in mouse cortical astrocytes. J. Neurosci. 2008, 28, 5473–5480.
  38. Lalo, U.; Palygin, O.; North, R.A.; Verkhratsky, A.; Pankratov, Y. Age-dependent remodelling of ionotropic signalling in cortical astroglia. Aging Cell 2011, 10, 392–402.
  39. Verkhratsky, A.; Pankratov, Y.; Lalo, U.; Nedergaard, M. P2X receptors in neuroglia. Wiley Interdiscip. Rev. Membr. Transp. Signal. 2012, 1, 151–161.
  40. Wang, Q.; Kong, Y.; Wu, D.-Y.; Liu, J.-H.; Jie, W.; You, Q.-L.; Huang, L.; Hu, J.; Chu, H.-D.; Gao, F.; et al. Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice. Nat. Commun. 2021, 12, 3321.
  41. Maruyama, S.; Boku, S.; Okazaki, S.; Kikuyama, H.; Mizoguchi, Y.; Monji, A.; Otsuka, I.; Sora, I.; Kanazawa, T.; Hishimoto, A.; et al. ATP and repetitive electric stimulation increases leukemia inhibitory factor expression in astrocytes: A potential role for astrocytes in the action mechanism of electroconvulsive therapy. Psychiatry Clin. Neurosci. 2020, 74, 311–317.
  42. Mah, W.; Lee, S.M.; Lee, J.; Bae, J.Y.; Ju, J.S.; Lee, C.J.; Ahn, D.K.; Bae, Y.C. A role for the purinergic receptor P2X3 in astrocytes in the mechanism of craniofacial neuropathic pain. Sci. Rep. 2017, 7, 13627.
  43. Fumagalli, M.; Brambilla, R.; D’Ambrosi, N.; Volonté, C.; Matteoli, M.; Verderio, C.; Abbracchio, M.P. Nucleotide-mediated calcium signaling in rat cortical astrocytes: Role of P2X and P2Y receptors. Glia 2003, 43, 218–230.
  44. Lee, J.; Bae, J.Y.; Lee, C.J.; Bae, Y.C. Electrophysiological Evidence for Functional Astrocytic P2X(3) Receptors in the Mouse Trigeminal Caudal Nucleus. Exp. Neurobiol. 2018, 27, 88–93.
  45. Franke, H.; Grosche, J.; Schädlich, H.; Krügel, U.; Allgaier, C.; Illes, P. P2X receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience 2001, 108, 421–429.
  46. Ashour, F.; Deuchars, J. Electron microscopic localisation of P2X4 receptor subunit immunoreactivity to pre- and post-synaptic neuronal elements and glial processes in the dorsal vagal complex of the rat. Brain Res. 2004, 1026, 44–55.
  47. Jabs, R.; Matthias, K.; Grote, A.; Grauer, M.; Seifert, G.; Steinhäuser, C. Lack of P2X receptor mediated currents in astrocytes and GluR type glial cells of the hippocampal CA1 region. Glia 2007, 55, 1648–1655.
  48. Muller, M.S.; Taylor, C.W. ATP evokes Ca(2+) signals in cultured foetal human cortical astrocytes entirely through G protein-coupled P2Y receptors. J. Neurochem. 2017, 142, 876–885.
  49. Loesch, A. On P2X receptors in the brain: Microvessels. Dedicated to the memory of the late Professor Geoffrey Burnstock (1929–2020). Cell Tissue Res. 2021, 384, 577–588.
  50. Kucher, B.M.; Neary, J.T. Bi-functional effects of ATP/P2 receptor activation on tumor necrosis factor-alpha release in lipopolysaccharide-stimulated astrocytes. J. Neurochem. 2005, 92, 525–535.
  51. Duan, S.; Anderson, C.M.; Keung, E.C.; Chen, Y.; Chen, Y.; Swanson, R.A. P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J. Neurosci. 2003, 23, 1320–1328.
  52. Panenka, W.; Jijon, H.; Herx, L.M.; Armstrong, J.N.; Feighan, D.; Wei, T.; Yong, V.W.; Ransohoff, R.M.; MacVicar, B.A. P2X7-like receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 expression via mitogen-activated protein kinase. J. Neurosci. 2001, 21, 7135–7142.
  53. Khan, M.T.; Deussing, J.; Tang, Y.; Illes, P. Astrocytic rather than neuronal P2X7 receptors modulate the function of the tri-synaptic network in the rodent hippocampus. Brain Res. Bull. 2019, 151, 164–173.
  54. Narcisse, L.; Scemes, E.; Zhao, Y.; Lee, S.C.; Brosnan, C.F. The cytokine IL-1beta transiently enhances P2X7 receptor expression and function in human astrocytes. Glia 2005, 49, 245–258.
  55. Martin, E.; Amar, M.; Dalle, C.; Youssef, I.; Boucher, C.; Le Duigou, C.; Brückner, M.; Prigent, A.; Sazdovitch, V.; Halle, A.; et al. New role of P2X7 receptor in an Alzheimer’s disease mouse model. Mol. Psychiatry 2019, 24, 108–125.
  56. Gandelman, M.; Peluffo, H.; Beckman, J.S.; Cassina, P.; Barbeito, L. Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: Implications for amyotrophic lateral sclerosis. J. Neuroinflamm. 2010, 7, 33.
  57. Calovi, S.; Mut-Arbona, P.; Sperlágh, B. Microglia and the Purinergic Signaling System. Neuroscience 2019, 405, 137–147.
  58. Brautigam, V.M.; Frasier, C.; Nikodemova, M.; Watters, J.J. Purinergic receptor modulation of BV-2 microglial cell activity: Potential involvement of p38 MAP kinase and CREB. J. Neuroimmunol. 2005, 166, 113–125.
  59. Seo, D.R.; Kim, S.Y.; Kim, K.Y.; Lee, H.G.; Moon, J.H.; Lee, J.S.; Lee, S.H.; Kim, S.U.; Lee, Y.B. Cross talk between P2 purinergic receptors modulates extracellular ATP-mediated interleukin-10 production in rat microglial cells. Exp. Mol. Med. 2008, 40, 19–26.
  60. Lewis, N.D.; Hill, J.D.; Juchem, K.W.; Stefanopoulos, D.E.; Modis, L.K. RNA sequencing of microglia and monocyte-derived macrophages from mice with experimental autoimmune encephalomyelitis illustrates a changing phenotype with disease course. J. Neuroimmunol. 2014, 277, 26–38.
  61. Bruttger, J.; Karram, K.; Wörtge, S.; Regen, T.; Marini, F.; Hoppmann, N.; Klein, M.; Blank, T.; Yona, S.; Wolf, Y.; et al. Genetic Cell Ablation Reveals Clusters of Local Self-Renewing Microglia in the Mammalian Central Nervous System. Immunity 2015, 43, 92–106.
  62. Xiang, Z.; Burnstock, G. Expression of P2X receptors on rat microglial cells during early development. Glia 2005, 52, 119–126.
  63. Janks, L.; Sharma, C.V.R.; Egan, T.M. A central role for P2X7 receptors in human microglia. J. Neuroinflamm. 2018, 15, 325.
  64. Chiu, I.M.; Morimoto, E.T.; Goodarzi, H.; Liao, J.T.; O’Keeffe, S.; Phatnani, H.P.; Muratet, M.; Carroll, M.C.; Levy, S.; Tavazoie, S.; et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 2013, 4, 385–401.
  65. Solga, A.C.; Pong, W.W.; Walker, J.; Wylie, T.; Magrini, V.; Apicelli, A.J.; Griffith, M.; Griffith, O.L.; Kohsaka, S.; Wu, G.F.; et al. RNA-sequencing reveals oligodendrocyte and neuronal transcripts in microglia relevant to central nervous system disease. Glia 2015, 63, 531–548.
  66. Bianco, F.; Fumagalli, M.; Pravettoni, E.; D’Ambrosi, N.; Volonte, C.; Matteoli, M.; Abbracchio, M.P.; Verderio, C. Pathophysiological roles of extracellular nucleotides in glial cells: Differential expression of purinergic receptors in resting and activated microglia. Brain Res. Brain Res. Rev. 2005, 48, 144–156.
  67. Beggs, S.; Trang, T.; Salter, M.W. P2X4R+ microglia drive neuropathic pain. Nat. Neurosci. 2012, 15, 1068–1073.
  68. Toyomitsu, E.; Tsuda, M.; Yamashita, T.; Tozaki-Saitoh, H.; Tanaka, Y.; Inoue, K. CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia. Purinergic Signal. 2012, 8, 301–310.
  69. Ulmann, L.; Hatcher, J.P.; Hughes, J.P.; Chaumont, S.; Green, P.J.; Conquet, F.; Buell, G.N.; Reeve, A.J.; Chessell, I.P.; Rassendren, F. Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J. Neurosci. 2008, 28, 11263–11268.
  70. Coull, J.A.; Beggs, S.; Boudreau, D.; Boivin, D.; Tsuda, M.; Inoue, K.; Gravel, C.; Salter, M.W.; De Koninck, Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005, 438, 1017–1021.
  71. Zabala, A.; Vazquez-Villoldo, N.; Rissiek, B.; Gejo, J.; Martin, A.; Palomino, A.; Perez-Samartín, A.; Pulagam, K.R.; Lukowiak, M.; Capetillo-Zarate, E.; et al. P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis. EMBO Mol. Med. 2018, 10.
  72. Guo, L.H.; Trautmann, K.; Schluesener, H.J. Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain. J. Neuroimmunol. 2005, 163, 120–127.
  73. Shieh, C.H.; Heinrich, A.; Serchov, T.; van Calker, D.; Biber, K. P2X7-dependent, but differentially regulated release of IL-6, CCL2, and TNF-α in cultured mouse microglia. Glia 2014, 62, 592–607.
  74. He, Y.; Taylor, N.; Fourgeaud, L.; Bhattacharya, A. The role of microglial P2X7: Modulation of cell death and cytokine release. J. Neuroinflamm. 2017, 14, 135.
  75. Martínez-Frailes, C.; Di Lauro, C.; Bianchi, C.; de Diego-García, L.; Sebastián-Serrano, Á.; Boscá, L.; Díaz-Hernández, M. Amyloid Peptide Induced Neuroinflammation Increases the P2X7 Receptor Expression in Microglial Cells, Impacting on Its Functionality. Front. Cell Neurosci. 2019, 13, 143.
  76. Sanz, J.M.; Chiozzi, P.; Ferrari, D.; Colaianna, M.; Idzko, M.; Falzoni, S.; Fellin, R.; Trabace, L.; Di Virgilio, F. Activation of microglia by amyloid requires P2X7 receptor expression. J. Immunol. 2009, 182, 4378–4385.
  77. Crabbé, M.; Van der Perren, A.; Bollaerts, I.; Kounelis, S.; Baekelandt, V.; Bormans, G.; Casteels, C.; Moons, L.; Van Laere, K. Increased P2X7 Receptor Binding Is Associated With Neuroinflammation in Acute but Not Chronic Rodent Models for Parkinson’s Disease. Front. Neurosci. 2019, 13, 799.
  78. Domercq, M.; Matute, C. Targeting P2X4 and P2X7 receptors in multiple sclerosis. Curr. Opin. Pharmacol. 2019, 47, 119–125.
  79. Wang, X.H.; Xie, X.; Luo, X.G.; Shang, H.; He, Z.Y. Inhibiting purinergic P2X7 receptors with the antagonist brilliant blue G is neuroprotective in an intranigral lipopolysaccharide animal model of Parkinson’s disease. Mol. Med. Rep. 2017, 15, 768–776.
  80. Ribeiro, D.E.; Roncalho, A.L.; Glaser, T.; Ulrich, H.; Wegener, G.; Joca, S. P2X7 Receptor Signaling in Stress and Depression. Int. J. Mol. Sci. 2019, 20, 2778.
  81. D’Ambrosi, N.; Finocchi, P.; Apolloni, S.; Cozzolino, M.; Ferri, A.; Padovano, V.; Pietrini, G.; Carrì, M.T.; Volonté, C. The proinflammatory action of microglial P2 receptors is enhanced in SOD1 models for amyotrophic lateral sclerosis. J. Immunol. 2009, 183, 4648–4656.
  82. Fabbrizio, P.; Amadio, S.; Apolloni, S.; Volonté, C. P2X7 Receptor Activation Modulates Autophagy in SOD1-G93A Mouse Microglia. Front. Cell Neurosci. 2017, 11, 249.
  83. Apolloni, S.; Amadio, S.; Parisi, C.; Matteucci, A.; Potenza, R.L.; Armida, M.; Popoli, P.; D’Ambrosi, N.; Volonté, C. Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. Dis. Model. Mech. 2014, 7, 1101–1109.
  84. Ly, D.; Dongol, A.; Cuthbertson, P.; Guy, T.V.; Geraghty, N.J.; Sophocleous, R.A.; Sin, L.; Turner, B.J.; Watson, D.; Yerbury, J.J.; et al. The P2X7 receptor antagonist JNJ-47965567 administered thrice weekly from disease onset does not alter progression of amyotrophic lateral sclerosis in SOD1(G93A) mice. Purinergic Signal. 2020, 16, 109–122.
  85. Agresti, C.; Meomartini, M.E.; Amadio, S.; Ambrosini, E.; Serafini, B.; Franchini, L.; Volonté, C.; Aloisi, F.; Visentin, S. Metabotropic P2 receptor activation regulates oligodendrocyte progenitor migration and development. Glia 2005, 50, 132–144.
  86. Kashfi, S.; Peymani, M.; Ghaedi, K.; Baharvand, H.; Nasr-Esfahani, M.H.; Javan, M. Purinergic Receptor Expression and Potential Association with Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cell Development. Cell J. 2017, 19, 386–402.
  87. Zhang, Y.; Chen, K.; Sloan, S.A.; Bennett, M.L.; Scholze, A.R.; O’Keeffe, S.; Phatnani, H.P.; Guarnieri, P.; Caneda, C.; Ruderisch, N.; et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 2014, 34, 11929–11947.
  88. Welsh, T.G.; Kucenas, S. Purinergic signaling in oligodendrocyte development and function. J. Neurochem. 2018, 145, 6–18.
  89. Matute, C.; Torre, I.; Pérez-Cerdá, F.; Pérez-Samartín, A.; Alberdi, E.; Etxebarria, E.; Arranz, A.M.; Ravid, R.; Rodríguez-Antigüedad, A.; Sánchez-Gómez, M.; et al. P2X(7) receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J. Neurosci. 2007, 27, 9525–9533.
  90. Morgan, J.; Alves, M.; Conte, G.; Menéndez-Méndez, A.; de Diego-Garcia, L.; de Leo, G.; Beamer, E.; Smith, J.; Nicke, A.; Engel, T. Characterization of the Expression of the ATP-Gated P2X7 Receptor Following Status Epilepticus and during Epilepsy Using a P2X7-EGFP Reporter Mouse. Neurosci. Bull. 2020, 36, 1242–1258.
  91. Domercq, M.; Perez-Samartin, A.; Aparicio, D.; Alberdi, E.; Pampliega, O.; Matute, C. P2X7 receptors mediate ischemic damage to oligodendrocytes. Glia 2010, 58, 730–740.
  92. Illes, P. P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases. Int. J. Mol. Sci. 2020, 21, 5996.
  93. Wareham, K.; Vial, C.; Wykes, R.C.; Bradding, P.; Seward, E.P. Functional evidence for the expression of P2X1, P2X4 and P2X7 receptors in human lung mast cells. Br. J. Pharmacol. 2009, 157, 1215–1224.
  94. Plum, T.; Wang, X.; Rettel, M.; Krijgsveld, J.; Feyerabend, T.B.; Rodewald, H.R. Human Mast Cell Proteome Reveals Unique Lineage, Putative Functions, and Structural Basis for Cell Ablation. Immunity 2020, 52, 404.e5–416.e5.
  95. Bonvini, S.J.; Birrell, M.A.; Dubuis, E.; Adcock, J.J.; Wortley, M.A.; Flajolet, P.; Bradding, P.; Belvisi, M.G. Novel airway smooth muscle-mast cell interactions and a role for the TRPV4-ATP axis in non-atopic asthma. Eur. Respir. J. 2020, 56.
  96. Wareham, K.J.; Seward, E.P. P2X7 receptors induce degranulation in human mast cells. Purinergic Signal. 2016, 12, 235–246.
  97. Yoshida, K.; Ito, M.; Matsuoka, I. Divergent regulatory roles of extracellular ATP in the degranulation response of mouse bone marrow-derived mast cells. Int. Immunopharmacol. 2017, 43, 99–107.
  98. Yoshida, K.; Tajima, M.; Nagano, T.; Obayashi, K.; Ito, M.; Yamamoto, K.; Matsuoka, I. Co-Stimulation of Purinergic P2X4 and Prostanoid EP3 Receptors Triggers Synergistic Degranulation in Murine Mast Cells. Int. J. Mol. Sci. 2019, 20, 5157.
  99. Yoshida, K.; Ito, M.A.; Sato, N.; Obayashi, K.; Yamamoto, K.; Koizumi, S.; Tanaka, S.; Furuta, K.; Matsuoka, I. Extracellular ATP Augments Antigen-Induced Murine Mast Cell Degranulation and Allergic Responses via P2X4 Receptor Activation. J. Immunol. 2020, 204, 3077–3085.
  100. Nurkhametova, D.; Kudryavtsev, I.; Guselnikova, V.; Serebryakova, M.; Giniatullina, R.R.; Wojciechowski, S.; Tore, F.; Rizvanov, A.; Koistinaho, J.; Malm, T.; et al. Activation of P2X7 Receptors in Peritoneal and Meningeal Mast Cells Detected by Uptake of Organic Dyes: Possible Purinergic Triggers of Neuroinflammation in Meninges. Front. Cell. Neurosci. 2019, 13.
  101. Galli, S.J.; Nakae, S.; Tsai, M. Mast cells in the development of adaptive immune responses. Nat. Immunol. 2005, 6, 135–142.
  102. Lundequist, A.; Pejler, G. Biological implications of preformed mast cell mediators. Cell Mol. Life Sci. 2011, 68, 965–975.
  103. Shimokawa, C.; Kanaya, T.; Hachisuka, M.; Ishiwata, K.; Hisaeda, H.; Kurashima, Y.; Kiyono, H.; Yoshimoto, T.; Kaisho, T.; Ohno, H. Mast Cells Are Crucial for Induction of Group 2 Innate Lymphoid Cells and Clearance of Helminth Infections. Immunity 2017, 46, 863.e4–874.e4.
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