P2X7, NMDA and BDNF receptors converge on GSK3 phosphorylation and cooperate to promote survival in cerebellar granule neurons

Ortega, Felipe; Pérez-Sen, Ráquel; Morente, Verónica; Delicado, Esmerilda G.; Miras-Portugal, Marı́a Teresa

doi:10.1007/s00018-010-0278-x

Cited by 62 publications

(50 citation statements)

References 35 publications

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“…When purified neuronal cultures were used, ATP and BzATP induced a consistent increase in cell viability, suggesting that activation of P2X7 receptors in retinal neurons in the absence of glial cells might be neuroprotective. These observations are in good agreement with recent findings showing that activation of P2X7 receptors is neuroprotective against PI3K/Akt inhibition in purified cultures of rat cerebellar granule cells [23,24] and the discrepancies between our findings and those mentioned before could be due to differences in the methodological conditions used. Zhang et al observed significant levels of ganglion cell death when freshly dissociated retinal cultures were incubated with BzATP.…”

Section: Discussionsupporting

confidence: 93%

“…Both P2X3 and P2X7 receptors were shown to inhibit axonal growth and branching of developing motor axons [19], cultured hippocampal neurons [21], and neuroblastoma cells [22]. Moreover, activation of P2X7 receptors was shown to promote the survival of cerebellar granule cells [23,24], but the death of cultured striatum-derived neural progenitors [25], a conflicting observation that now can be explained by the recent detection and characterization of P2X7 receptor splice variants with distinct functional properties [26,27]. While P2X7A receptor induces cell permeabilization and death, the truncated P2X7B receptor that lacks the carboxy-terminal induces cell growth.…”

Section: Introductionmentioning

confidence: 99%

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ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors

Anccasi

Ornelas

Cossenza

et al. 2012

Purinergic Signalling

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Previous data suggest that nucleotides are important mitogens in the developing retina. Here, the effect of ATP on the death of cultured chick embryo retina cells was investigated. In cultures obtained from retinas of 7-day-old chick embryos (E7) that were cultivated for 2 days (E7C2), both ATP and BzATP induced a ∼30 % decrease in cell viability that was time-and dose-dependent and that could be blocked by 0.2 mM oxidized ATP or 0.3 μM KN-62. An increase in cleaved caspase-3 levels and in the number of TUNELpositive cells was observed when cultures were incubated with 3 mM ATP and immunolabeling for cleaved-caspase 3 was observed over neurons but not over glial cells. ATPdependent cell death was developmentally regulated, the maximal levels being detected by E7C2-3. Nucleotides were able to increase neuronal ethidium bromide and sulforhodamine B uptake in mixed and purified neuronal cultures, an effect that was blocked by the antagonists Brilliant Blue G and oxidized ATP. In contrast, nucleotide-induced cell death was observed only in mixed cultures, but not in purified cultures of neurons or glia. ATP-induced neuronal death was blocked by the glutamatergic antagonists MK801 and DNQX and activation of P2X7 receptors by ATP decreased the uptake of [ These results suggest that ATP induces apoptosis of chick embryo retinal neurons in culture through activation of P2X7 and glutamate ionotropic receptors. Involvement of a P2X7 receptor-mediated inhibition of the glial uptake of glutamate is suggested.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors

Anccasi

Ornelas

Cossenza

et al. 2012

Purinergic Signalling

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“…The speed with which β-catenin is activated suggests that P2X7 regulates the stability of β-catenin as opposed to its gene expression at early time points. In this regard, we showed that P2X7 activation in osteoblast-like cells rapidly inhibits GSK3β in a PKCdependent manner in agreement with previous findings in cerebellar granule neurons [13,22]. Interestingly, the PTH-PTH 1 receptor complex has also been shown to facilitate canonical Wnt signaling through inhibition of GSK3β in osteoblast-like SaOS-2 cells [28].…”

Section: P2x7 Potentiates the Wnt/β-catenin Pathwaysupporting

confidence: 91%

“…In cerebellar granule neurons, activation of P2X7 has been shown to inhibit GSK3β through mechanisms dependent on protein kinase C (PKC) [13,22]. Previous work from our lab has demonstrated that stimulation of P2X7 in osteoblasts activates Ca 2+ signaling and the phosphatidylinositol 3-kinase (PI3K) pathway [17,23].…”

Section: Activation Of P2x7 Increases Inhibitory Phosphorylation Of Gmentioning

confidence: 99%

P2X7 nucleotide receptor signaling potentiates the Wnt/β-catenin pathway in cells of the osteoblast lineage

Grol

Brooks

Pereverzev

et al. 2016

Purinergic Signalling

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The P2X7 and Wnt/β-catenin signaling pathways regulate osteoblast differentiation and are critical for the anabolic responses of bone to mechanical loading. However, whether these pathways interact to control osteoblast activity is unknown. The purpose of this study was to investigate the effects of P2X7 activation on Wnt/β-catenin signaling in osteoblasts. Using MC3T3-E1 cells, we found that combined treatment with Wnt3a and the P2X7 agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate (BzATP) elicited more sustained β-catenin nuclear localization than that induced by Wnt3a alone. Wnt3a-induced increases in β-catenin transcriptional activity were also potentiated by treatment with BzATP. Consistent with involvement of P2X7, a high ATP concentration (1 mM) potentiated Wnt3a-induced β-catenin transcriptional activity, whereas a low concentration (10 μM) of ATP, adenosine 5′-diphosphate (ADP), or uridine 5′-triphosphate (UTP) failed to elicit a response. The potentiation of β-catenin transcriptional activity elicited by BzATP was also inhibited by two distinct P2X7 antagonists: A 438079 and A 740003. Furthermore, responses to Wnt3a in calvarial cells isolated from P2rx7 knockout mice were significantly less than in cells from wild-type controls. In MC3T3-E1 cells, BzATP increased inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), a process that was blocked by A 438079 and diminished by inhibition of protein kinase C. Thus, P2X7 signaling may potentiate the canonical Wnt pathway through GSK3β inhibition. Taken together, we show that P2X7 activation prolongs and potentiates Wnt/β-catenin signaling. Consequently, cross-talk between P2X7 and Wnt/β-catenin pathways may modulate osteoblast activity in response to mechanical loading.

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“…In contrast to their accepted contribution to neurodegeneration, neuroprotective actions of P2X7 receptors have also been reported (Skaper et al, 2010). In rat cerebellar granule neurons, P2X7 receptors activate a survival pathway alternative to that of the classic neurotrophic factors, depending on protein kinase C activation but converging on glycogen synthase kinase-3 inhibition to promote neuronal survival (Ortega et al, 2010). P2X7 receptors could also be involved in neuronal development.…”

Section: Introductionmentioning

confidence: 99%

Purinergic P2X7 Receptors Mediate Cell Death in Mouse Cerebellar Astrocytes in Culture

Salas

Carrasquero

Olivos-Oré

et al. 2013

J Pharmacol Exp Ther

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The brain distribution and functional role of glial P2X7 receptors are broader and more complex than initially anticipated. We characterized P2X7 receptors from cerebellar astrocytes at the molecular, immunocytochemical, biophysical, and cell physiologic levels. Mouse cerebellar astrocytes in culture express mRNA coding for P2X7 receptors, which is translated into P2X7 receptor protein as proven by Western blot analysis and immunocytochemistry. Fura-2 imaging showed cytosolic calcium responses to ATP and the synthetic analog 39-O-(4-benzoyl)benzoyl-ATP (BzATP) exhibited two components, namely an initial transient and metabotropic component followed by a sustained one that depended on extracellular calcium. This latter component, which was absent in astrocytes from P2X7 receptor knockout mice (P2X7 KO), was modulated by extracellular Mg 21, and was sensitive to Brilliant Blue G (BBG) and 3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine (A438079) antagonism. BzATP also elicited inwardly directed nondesensitizing whole-cell ionic currents that were reduced by extracellular Mg 21 and P2X7 antagonists (BBG and calmidazolium). In contrast to that previously reported in rat cerebellar astrocytes, sustained BzATP application induced a gradual increase in membrane permeability to large cations, such as N-methyl-D-glucamine and 4-[3-methyl-2(3H)-benzoxazolylidene)-methyl]-1-[3-(triethylammonio)propyl]diiodide, which ultimately led to the death of mouse astrocytes. Cerebellar astrocyte cell death was prevented by BBG but not by calmidazolium, removal of extracellular calcium, or treatment with the caspase-3 inhibitor, benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone, thus suggesting a necrotictype mechanism of cell death. Since this cellular response was not observed in astrocytes from P2X7 KO mice, this study suggests that stimulation of P2X7 receptor may convey a cell death signal to cerebellar astrocytes in a species-specific manner.

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P2X7, NMDA and BDNF receptors converge on GSK3 phosphorylation and cooperate to promote survival in cerebellar granule neurons

Cited by 62 publications

References 35 publications

ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors

ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors

P2X7 nucleotide receptor signaling potentiates the Wnt/β-catenin pathway in cells of the osteoblast lineage

Purinergic P2X7 Receptors Mediate Cell Death in Mouse Cerebellar Astrocytes in Culture

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