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Rodrigues, R.J.;  Figueira, A.S.;  Marques, J.M. P2Y1 Receptor as a Catalyst of Brain Neurodegeneration. Encyclopedia. Available online: (accessed on 20 April 2024).
Rodrigues RJ,  Figueira AS,  Marques JM. P2Y1 Receptor as a Catalyst of Brain Neurodegeneration. Encyclopedia. Available at: Accessed April 20, 2024.
Rodrigues, Ricardo J., Ana S. Figueira, Joana M. Marques. "P2Y1 Receptor as a Catalyst of Brain Neurodegeneration" Encyclopedia, (accessed April 20, 2024).
Rodrigues, R.J.,  Figueira, A.S., & Marques, J.M. (2022, November 18). P2Y1 Receptor as a Catalyst of Brain Neurodegeneration. In Encyclopedia.
Rodrigues, Ricardo J., et al. "P2Y1 Receptor as a Catalyst of Brain Neurodegeneration." Encyclopedia. Web. 18 November, 2022.
P2Y1 Receptor as a Catalyst of Brain Neurodegeneration

Different brain disorders display distinctive etiologies and pathogenic mechanisms. However, they also share pathogenic events. One event systematically occurring in different brain disorders, both acute and chronic, is the increase of the extracellular ATP levels. Accordingly, several P2 (ATP/ADP) and P1 (adenosine) receptors, as well as the ectoenzymes involved in the extracellular catabolism of ATP, have been associated to different brain pathologies, either with a neuroprotective or neurodegenerative action. The P2Y1 receptor (P2Y1R) is one of the purinergic receptors associated to different brain diseases. It has a widespread regional, cellular, and subcellular distribution in the brain, it is capable of modulating synaptic function and neuronal activity, and it is particularly important in the control of astrocytic activity and in astrocyte–neuron communication. In diverse brain pathologies, there is growing evidence of a noxious gain-of-function of P2Y1R favoring neurodegeneration by promoting astrocyte hyperactivity, entraining Ca2+-waves, and inducing the release of glutamate by directly or indirectly recruiting microglia and/or by increasing the susceptibility of neurons to damage.

P2Y1 receptor neurodegeneration ATP ADP brain

1. P2Y1 Receptor in Neurodegenerative Disorders

An increase in the expression levels of P2Y1 receptor (P2Y1R) has been documented in different acute or chronic neurological disorders such as epilepsy [1][2][3], mechanical injury [4], ischemia [5], or Alzheimer’s disease (AD) [6][7], which suggests the gain of a noxious function of P2Y1R. Accordingly, compelling evidence have been associating P2Y1R with different acute and chronic brain disorders.
In ischemic conditions such as oxygen–glucose deprivation (OGD), the blockade of P2Y1R prevented the depression of field excitatory postsynaptic potentials and anoxic depolarization in rat hippocampal slices, also preventing CA1 pyramidal neuronal damage [8][9]. Similar neuroprotection was afforded by the i.c.v. administration of a selective antagonist of P2Y1R after transient middle cerebral artery occlusion in rats, reducing infarct volume and recovering motor coordination [5]. Moreover, P2Y1R-KO mice displayed reduced hippocampal damage and no cognitive decline upon middle cerebral artery occlusion, an effect mimicked by the pharmacological blockade of P2Y1R in rodents [10]. This has been associated to the control of astrocytic function and glial neuroinflammatory response [5][10][11]. However, neuronal mechanisms should also be involved in the deleterious contribution of P2Y1R in ischemic conditions since in another study, it was observed that P2Y1R blockade attenuated neuronal damage and cognitive performance induced by permanent middle cerebral artery occlusion, without inhibiting the astrocytic or microglial reactivity [12]. On the other hand, a neuroprotective action of P2Y1R has been also reported in ischemia. P2Y1R-KO mice displayed a higher number of injured hippocampal neurons upon OGD [13] and in mouse ischemic models of photo-thrombolysis, a reduction of neuronal damage was observed with the activation of astrocytic P2Y1R [14][15]. A similar neuroprotection provided by astrocytic P2Y1R was observed in oxidative stress through IL-6 release [16]. A neuroprotective vs. neurodegenerative action of P2Y1R may be due to either the degree of P2Y1R-driven activity and/or a time-dependent gain of a noxious function of P2Y1R, shifting astrocytes from a supportive role to a deleterious impact and/or a time-dependent differential impact of neuronal and glial P2Y1R. A similar time-dependent shift from a neuroprotective to a neurodegenerative input of P2Y1R was observed in excitotoxicity. P2Y1R was shown to be required for glutamate-induced synaptic loss and subsequent neuronal death in the rat hippocampus both in vitro and in vivo [17]. This is due at least in part to a P2Y1R-driven increase of NMDARs at the axon, leading to a deleterious Ca2+-entry and subsequent calpain-mediated axonal cytoskeleton damage [17]. However, it also provided evidence that P2Y1R may reduce AMPAR, decreasing the susceptibility of neurons to excitotoxicity [18]. In SE-induced neurodegeneration, the i.c.v. injection of a selective antagonist of P2Y1R reduced hippocampal neuronal death observed with the systemic i.p. administration of KA [17]. However, in a more recent study, it was detailed that there is a time-dependent shift from a neuroprotective to a neurodegenerative contribution of P2Y1R to SE-induced neurodegeneration, correlated with a different impact in SE-induced seizure activity. Using intra-amygdala KA and pilocarpine mouse models, while the antagonism of P2Y1R before SE induction increased seizure activity and neurodegeneration in the hippocampus, the blockade of P2Y1R shortly after the onset of SE reduced seizure activity and degeneration [19]. It was suggested that this may be due to a time-dependent contribution of neuronal and astrocytic P2Y1R [19]. Neuronal P2Y1R can reduce hyperexcitability, either by directly depressing postsynaptic NMDARs [17][20] and/or by a circuit-driven increase of the inhibitory tonus [21][22]; however, then the recruitment of astrocytes and the P2Y1R-induced release of glutamate [23], subsequently activating NMDAR on neurons [24], can lead to hyperexcitability [25][26][27][28]. In addition, this time-dependent neuroprotective to neurodegenerative shift may also be due to the fact that the contribution of neuronal and astrocytic P2Y1Rs may also change at different pathogenic stages. For instance, neuronal P2Y1R tonically depresses dendritic NMDARs, but in excitotoxic conditions, it induces a toxic increase in axonal NMDARs [17]. Interestingly, a similar P2Y1R-driven increase in NMDARs was found in the dorsal root ganglion underlying remifentanil-induced postoperative hyperalgesia [29]. However, this contribution of neuronal P2Y1R to neurodegeneration fades with more intense excitotoxic conditions [17]. Regarding the contribution of astrocytic P2Y1R, astrocytes have a physiological supportive role to neuronal function, namely, glutamate uptake or the release of neurotrophic factors [30] and, as mentioned, astrocytic P2Y1R can have a neuroprotective effect as observed in ischemia, oxidative stress [14][15][16], and TBI (see below) [31]. Nevertheless, the evidence so far provided essentially point to a net neurodegenerative contribution of P2Y1R in excitotoxic conditions. There is an increased density of P2Y1R upon SE as well as in human tissue from temporal lobe epilepsy patients [2][3], supporting microglia and astrocytic-induced hyperexcitability through the P2Y1R-induced release of glutamate from astrocytes [3][27][32]. This is further heralded by the observation that the blockade of P2Y1R post-SE delayed the onset of epilepsy and suppressed epileptic seizures in a reversible manner [19]. In addition to a control of seizure severity, the antagonism of P2Y1R may be also beneficial against epilepsy comorbidities since the blockade of P2Y1R rescued synaptic plasticity, associated to a normalization of astroglial Ca2+-activity in epileptic hippocampus [32]
The blockade of P2Y1Rs also afforded neuroprotection upon TBI even in remote regions from the injury site, improving cognitive outcomes [33]. This effect was dependent on P2Y1R-mediated astrocytic Ca2+-waves and on NMDAR activation [33], indicating an exacerbation/propagation of neuronal injury through a P2Y1R-driven release of glutamate from astrocytes. This is further sustained by the release of ATP in regions distant to the impact point [34]. In addition to having control of astrocytes, it was more recently shown that the blockade of P2Y1R suppressed microglial activation at the injury site [35]. Moreover, evidence was provided that microglia recruited to the injury core is important for the formation of neuroprotective astrocyte scar in the peri-injured region by downregulating P2Y1R in astrocytes [31]. Hence, the neuroprotection afforded by the inhibition of P2Y1R in TBI may be due by the concomitant promotion of a protective scar around the lesion, mimicking the beneficial effects of microglia but inhibiting the microglia-mediated inflammatory response and avoiding the astrocytic-driven hyperexcitability involved in the exacerbation and propagation of neuronal injury.

2. P2Y1 Receptor as a Catalyst of Neurodegeneration

The major mechanism by which P2Y1R favors neurodegeneration, shared by different brain disorders, is its ability to control astrocytic function, thus entraining Ca2+-waves, inducing the release of inflammatory cytokines [5], and promoting the release of glutamate [3][23][27][32][33], ultimately leading to hyperexcitability and neuronal damage [24][25][26][27][28]. P2Y1R inhibition is also neuroprotective by allowing the development of neuroprotective astrocytic scars, namely in TBI [31]. These deleterious mechanisms of astrocytic P2Y1R are further sustained/enhanced by P2Y1R itself due to its ability to prevent astrocytic damage upon different noxious insults [36][37][38][39] and by mediating the autocrine signaling, inducing a sustained release of ATP from astrocytes [6][27][34][40][41]. This mechanism can be also sustained or potentiated by microglia recruitment through the release of ATP and subsequent P2Y1R-driven stimulation of astrocytes, promoting glutamatergic gliotransmission with an impact in synaptic activity [42], tethering inflammation to synaptic failure. Besides, although the role of P2Y1R in microglia remains elusive, it has been shown that, either directly or indirectly, P2Y1R is involved in the recruitment of microglia in epileptic phenomena [3] in TBI [35] and in ischemia [10]. In addition, neuronal P2Y1R may also contribute to neurodegeneration [12][17], namely, by favoring the initial synaptic loss and later neuronal death by a subcellular-specific upregulation of NMDARs, increasing their density in axons, leading to an initial Ca2+-driven calpain-mediated axonal cytoskeleton damage [17]. Altogether, the ability of P2Y1R to promote astrocyte hyperactivity and consequent glutamate release, to recruit and eventually format microglia response, and to directly increase the susceptibility of neurons to damage, indicate that P2Y1R is endowed with a transcellular capability to catalyze neurodegeneration in different brain disorders (Figure 1), both at the early onset [17][19] and at a chronic stage [6][19][43].
Figure 1. Schematic illustration depicting the transcellular capability of P2Y1R to catalyze neurodegeneration: (i) astrocytic hyperactivity; (ii) release of glutamate from astrocytes; (iii) depression of synaptic activity; and (iv) early axonal degeneration, synaptic loss, and later neuronal death.
The contribution of the purinergic signaling system to brain pathologies is not limited to P2Y1R. Other P2Rs, adenosine P1Rs, or ectoenzymes involved in the extracellular metabolism of ATP have been associated to the pathogenesis of different brain disorders, displaying both neurodegenerative actions, namely P2X7R, A2AR, and CD73 [44][45][46], and neuroprotective actions such as with P2Y2, P2Y4, P2Y12, and P2Y13 receptors (e.g., [36][47][48][49]). Hence, in order to fully comprehend the pathological contribution of P2Y1R to brain disorders and its potential value as a therapeutic target, it is fundamental to contextualize it within the purinergic signaling system. It will be important to understand the hierarchy, cooperation, and/or redundancy between the different elements that comprise the purinergic signaling system and understand how the contribution of purinergic signaling in pathological conditions is orchestrated. Some studies started to shed light on this topic. Besides the contribution of different purinergic receptors to the release of ATP such as P2X7R or A2AR [44][50][51][52], microglia P2Y13R prevents astrocyte proliferation induced by P2Y1R [53], and more recently, it was shown that A2AR physiologically reduces P2Y1R-driven Ca2+ increases in astrocytes, an effect blunted by Aßexposure [54]. This will allow a better comprehension of the contribution of P2Y1R to neurodegeneration, which is fundamental to define an eventual therapeutic strategy targeting P2Y1R, either directly or indirectly, to prevent its deleterious contribution. This may involve a multitarget time-dependent strategy. Since a sustained ATP release and the pathogenic involvement of P2Y1R is an event shared by different acute and chronic brain disorders, such a strategy targeting P2Y1R function may bring a sole therapeutic intervention to the different neurodegenerative disorders.


  1. Padrão, R.A.; Ariza, C.B.; Canzian, M.; Porcionatto, M.; Araffljo, M.G.L.; Cavalheiro, E.A. The P2 purinergic receptors are increased in the hippocampus of patients with temporal lobe epilepsy: What is the relevance to the epileptogenesis? Purinergic Signal. 2011, 7, 127.
  2. Alves, M.; Gomez-Villafuertes, R.; Delanty, N.; Farrell, M.A.; O’Brien, D.F.; Miras-Portugal, M.T.; Hernandez, M.D.; Henshall, D.C.; Engel, T. Expression and function of the metabotropic purinergic P2Y receptor family in experimental seizure models and patients with drug-refractory epilepsy. Epilepsia 2017, 58, 1603–1614.
  3. Alves, M.; Smith, J.; Engel, T. Differential expression of the metabotropic P2Y receptor family in the cortex following status epilepticus and neuroprotection via P2Y1 antagonism in mice. Front. Pharmacol. 2020, 10, 1558.
  4. Franke, H.; Krugel, U.; Grosche, J.; Heine, C.; Hartig, W.; Allgaier, C.; Illes, P. P2Y receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience 2004, 127, 431–441.
  5. Kuboyama, K.; Harada, H.; Tozaki-Saitoh, H.; Tsuda, M.; Ushijima, K.; Inoue, K. Astrocytic P2Y(1) receptor is involved in the regulation of cytokine/chemokine transcription and cerebral damage in a rat model of cerebral ischemia. J. Cereb. Blood Flow Metab. 2011, 31, 1930–1941.
  6. Delekate, A.; Fuchtemeier, M.; Schumacher, T.; Ulbrich, C.; Foddis, M.; Petzold, G.C. Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an alzheimer’s disease mouse model. Nat. Commun. 2014, 5, 5422.
  7. Moore, D.; Iritani, S.; Chambers, J.; Emson, P. Immunohistochemical localization of the P2Y1 purinergic receptor in Alzheimer’s disease. Neuroreport 2000, 11, 3799–3803.
  8. Traini, C.; Pedata, F.; Cipriani, S.; Mello, T.; Galli, A.; Giovannini, M.G.; Cerbai, F.; Volpini, R.; Cristalli, G.; Pugliese, A.M. P2 receptor antagonists prevent synaptic failure and extracellular signal-regulated kinase 1/2 activation induced by oxygen and glucose deprivation in rat CA1 hippocampus in vitro. Eur. J. Neurosci. 2011, 33, 2203–2215.
  9. Maraula, G.; Lana, D.; Coppi, E.; Gentile, F.; Mello, T.; Melani, A.; Galli, A.; Giovannini, M.G.; Pedata, F.; Pugliese, A.M. The selective antagonism of P2X7 and P2Y1 receptors prevents synaptic failure and affects cell proliferation induced by oxygen and glucose deprivation in rat dentate gyrus. PLoS ONE 2014, 9, e115273.
  10. Chin, Y.; Kishi, M.; Sekino, M.; Nakajo, F.; Abe, Y.; Terazono, Y.; Hiroyuki, O.; Kato, F.; Koizumi, S.; Gachet, C.; et al. Involvement of glial P2Y1 receptors in cognitive deficit after focal cerebral stroke in a rodent model. J. Neuroinflamm. 2013, 10, 95.
  11. Sun, J.J.; Liu, Y.; Ye, Z.R. Effects of P2Y1 receptor on glial fibrillary acidic protein and glial cell line-derived neurotrophic factor production of astrocytes under ischemic condition and the related signaling pathways. Neurosci. Bull. 2008, 24, 231–243.
  12. Carmo, M.R.; Simões, A.P.; Fonteles, A.A.; Souza, C.M.; Cunha, R.A.; Andrade, G.M. ATP P2Y1 receptors control cognitive deficits and neurotoxicity but not glial modifications induced by brain ischemia in mice. Eur. J. Neurosci. 2014, 39, 614–622.
  13. Fukumoto, Y.; Tanaka, K.F.; Parajuli, B.; Shibata, K.; Yoshioka, H.; Kanemaru, K.; Gachet, C.; Ikenaka, K.; Koizumi, S.; Kinouchi, H. Neuroprotective effects of microglial P2Y1 receptors against ischemic neuronal injury. J. Cereb. Blood Flow Metab. 2019, 39, 2144–2156.
  14. Zheng, W.; Watts, L.T.; Holstein, D.M.; Wewer, J.; Lechleiter, J.D. P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse. J. Cereb. Blood Flow Metab. 2013, 33, 600–611.
  15. Zheng, W.; Watts, L.T.; Holstein, D.M.; Prajapati, S.I.; Keller, C.; Grass, E.H.; Walter, C.A.; Lechleiter, J.D. Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. PLoS ONE 2010, 5, e14401.
  16. Fujita, T.; Tozaki-Saitoh, H.; Inoue, K. P2Y1 receptor signaling enhances neuroprotection by astrocytes against oxidative stress via IL-6 release in hippocampal cultures. Glia 2009, 57, 244–257.
  17. Simões, A.P.; Silva, C.G.; Marques, J.M.; Pochmann, D.; Porciúncula, L.O.; Ferreira, S.; Oses, J.P.; Beleza, R.O.; Real, J.I.; Köfalvi, A.; et al. Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation. Cell Death Dis. 2018, 9, 297.
  18. Maiolino, M.; O’Neill, N.; Lariccia, V.; Amoroso, S.; Sylantyev, S.; Angelova, P.R.; Abramov, A.Y. Inorganic polyphosphate regulates AMPA and NMDA receptors and protects against glutamate excitotoxicity via activation of P2Y receptors. J. Neurosci. 2018, 39, 6038–6048.
  19. Alves, M.; De Diego Garcia, L.; Conte, G.; Jimenez-Mateos, E.M.; D’Orsi, B.; Sanz-Rodriguez, A.; Prehn, J.H.M.; Henshall, D.C.; Engel, T. Context-specific switch from anti- to pro-epileptogenic function of the P2Y1 receptor in experimental epilepsy. J. Neurosci. 2019, 39, 5377–5392.
  20. Luthardt, J.; Borvendeg, S.J.; Sperlagh, B.; Poelchen, W.; Wirkner, K.; Illes, P. P2Y1 receptor activation inhibits NMDA receptor-channels in layer V pyramidal neurons of the rat prefrontal and parietal cortex. Neurochem. Int. 2003, 42, 161–172.
  21. Bowser, D.N.; Khakh, B.S. ATP excites interneurons and astrocytes to increase synaptic inhibition in neuronal networks. J. Neurosci. 2004, 24, 8606–8620.
  22. Kawamura, M.; Gachet, C.; Inoue, K.; Kato, F. Direct excitation of inhibitory interneurons by extracellular ATP mediated by P2Y1 receptors in the hippocampal slice. J. Neurosci. 2004, 24, 10835–41085.
  23. Domercq, M.; Brambilla, L.; Pilati, E.; Marchaland, J.; Volterra, A.; Bezzi, P. P2Y1 receptor-evoked glutamate exocytosis from astrocytes: Control by tumor necrosis factor-alpha and prostaglandins. J. Biol. Chem. 2006, 281, 30684–93066.
  24. Jourdain, P.; Bergersen, L.H.; Bhaukaurally, K.; Bezzi, P.; Santello, M.; Domercq, M.; Matute, C.; Tonello, F.; Gundersen, V.; Volterra, A. Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 2007, 10, 331–339.
  25. Engel, T.; Smith, J.; Alves, M. Targeting neuroinflammation via purinergic P2 receptors for disease modification in drug-refractory epilepsy. J. Inflamm. Res. 2021, 14, 3367–3392.
  26. Shen, W.; Nikolic, L.; Meunier, C.; Pfrieger, F.; Audinat, E. An autocrine purinergic signaling controls astrocyte-induced neuronal excitation. Sci. Rep. 2017, 7, 11280.
  27. Nikolic, L.; Shen, W.; Nobili, P.; Virenque, A.; Ulmann, L.; Audinat, E. Blocking TNFα-driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis. Glia 2018, 66, 2673–2683.
  28. Nobili, P.; Shen, W.; Milicevic, K.; Bogdanovic Pristov, J.; Audinat, E.; Nikolic, L. Therapeutic potential of astrocyte purinergic signalling in epilepsy and multiple sclerosis. Front. Pharmacol. 2022, 13, 900337.
  29. Su, L.; Bai, X.; Niu, T.; Zhuang, X.; Dong, B.; Wang, G.; Yu, Y. P2Y1 purinergic receptor inhibition attenuated remifentanil-induced postoperative hyperalgesia via decreasing NMDA receptor phosphorylation in dorsal root ganglion. Brain Res. Bull. 2021, 177, 352–362.
  30. Nedergaard, M.; Dirnagl, U. Role of glial cells in cerebral ischemia. Glia 2005, 50, 281–286.
  31. Shinozaki, Y.; Shibata, K.; Yoshida, K.; Shigetomi, E.; Gachet, C.; Ikenaka, K.; Tanaka, K.F.; Koizumi, S. Transformation of astrocytes to a neuroprotective phenotype by microglia via P2Y1 receptor downregulation. Cell Rep. 2017, 19, 1151–1164.
  32. Martorell, A.; Wellmann, M.; Guiffa, F.; Fuenzalida, M.; Bonansco, C. P2Y1 receptor inhibition rescues impaired synaptic plasticity and astroglial Ca2+-dependent activity in the epileptic hippocampus. Neurobiol. Dis. 2020, 146, 105132.
  33. Choo, A.M.; Miller, W.J.; Chen, Y.C.; Nibley, P.; Patel, T.P.; Goletiani, C.; Morrison, B., 3rd; Kutzing, M.K.; Firestein, B.L.; Sul, J.Y.; et al. Antagonism of purinergic signalling improves recovery from traumatic brain injury. Brain 2013, 136, 65–80.
  34. Moro, N.; Ghavim, S.S.; Sutton, R.L. Massive efflux of adenosine triphosphate into the extracellular space immediately after experimental traumatic brain injury. Exp. Ther. Med. 2021, 21, 575.
  35. Kumagawa, T.; Moro, N.; Maeda, T.; Kobayashi, M.; Furukawa, Y.; Shijo, K.; Yoshino, A. Anti-inflammatory effect of P2Y1 receptor blocker MRS2179 in a rat model of traumatic brain injury. Brain Res. Bull. 2022, 181, 46–54.
  36. Forster, D.; Reiser, J. Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies. Purinergic Signal. 2015, 11, 441–454.
  37. Shinozaki, Y.; Koizumi, S.; Ishida, S.; Sawada, J.; Ohno, Y.; Inoue, K. Cytoprotection against oxidative stress-induced damage of astrocytes by extracellular ATP via P2Y1 receptors. Glia 2005, 49, 288–300.
  38. Shinozaki, Y.; Koizumi, S.; Ohno, Y.; Nagao, T.; Inoue, K. Extracellular ATP counteracts the ERK1/2-mediated death-promoting signaling cascades in astrocytes. Glia 2006, 54, 606–618.
  39. Guo, H.; Liu, Z.Q.; Zhou, H.; Wang, Z.L.; Tao, Y.H.; Tong, Y. P2Y1 receptor antagonists mitigate oxygen and glucose deprivation-induced astrocyte injury. Mol. Med. Rep. 2018, 17, 1819–1824.
  40. Locovei, S.; Wang, J.; Dahl, G. Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium. FEBS Lett. 2006, 580, 239–244.
  41. Miller, W.J.; Leventhal, I.; Scarsella, D.; Haydon, P.G.; Janmey, P.; Meaney, D.F. Mechanically induced reactive gliosis causes ATP-mediated alterations in astrocyte stiffness. J. Neurotrauma 2009, 26, 789–797.
  42. Pascual, O.; Achour, S.B.; Rostaing, P.; Triller, A.; Bessis, A. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc. Natl. Acad. Sci. USA 2012, 109, E197–E205.
  43. Reichenbach, N.; Delekate, A.; Breithausen, B.; Keppler, K.; Poll, S.; Schulte, T.; Peter, J.; Plescher, M.; Hansen, J.N.; Blank, N.; et al. P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model. J. Exp. Med. 2018, 215, 1649–1663.
  44. Rodrigues, R.J.; Tomé, A.R.; Cunha, R.A. ATP as a multi-target danger signal in the brain. Front. Neurosci. 2015, 9, 148.
  45. Illes, P. P2X7 receptors amplify CNS damage in neurodegenerative diseases. Int. J. Mol. Sci. 2020, 21, 5996.
  46. Cunha, R.A. How does adenosine control neuronal dysfunction and neurodegeneration? J. Neurochem. 2016, 139, 1019–1055.
  47. Miras-Portugal, M.T.; Queipo, M.J.; Gil-Redondo, J.C.; Ortega, F.; Gómez-Villafuertes, R.; Gualix, J.; Delicado, E.G.; Pérez-Sen, R. P2 receptor interaction and signalling cascades in neuroprotection. Brain Res. Bull. 2019, 151, 74–83.
  48. Guzman, S.J.; Gerevich, Z. P2Y receptors in synaptic transmission and plasticity: Therapeutic potential in cognitive dysfunction. Neural Plast. 2016, 2016, 1207393.
  49. Woods, L.T.; Ajit, D.; Camden, J.M.; Erb, L.; Weisman, G.A. Purinergic receptors as potential therapeutic targets in Alzheimer’s disease. Neuropharmacology 2016, 104, 169–179.
  50. Madeira, D.; Dias, L.; Santos, P.; Cunha, R.A.; Canas, P.M.; Agostinho, P. Association between adenosine A2A receptors and connexin 43 regulates hemichannels activity and ATP release in astrocytes exposed to amyloid-β peptides. Mol. Neurobiol. 2021, 58, 6232–6248.
  51. Duan, S.; Neary, J.T. P2X7 receptors: Properties and relevance to CNS function. Glia 2006, 54, 738–746.
  52. 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.
  53. Quintas, C.; Vale, N.; Gonçalves, J.; Queiroz, G. Microglia P2Y13 receptors prevent astrocyte proliferation mediated by P2Y1 receptors. Front. Pharmacol. 2018, 9, 418.
  54. Dias, L.; Madeira, D.; Dias, R.; Tomé, Â.R.; Cunha, R.A.; Agostinho, P. Aβ1-42 peptides blunt the adenosine A2A receptor-mediated control of the interplay between P2X7 and P2Y1 receptors mediated calcium responses in astrocytes. Cell. Mol. Life Sci. 2022, 79, 457.
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Update Date: 21 Nov 2022