P2X7 Nucleotide Receptor is Coupled to GSK-3 Inhibition and Neuroprotection in Cerebellar Granule Neurons

Ortega, Felipe; Pérez-Sen, Ráquel; Delicado, Esmerilda G.; Miras‐Portugal, M. Teresa

doi:10.1007/s12640-009-9020-6

Cited by 48 publications

(43 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 92%

“…In the present study, we provide the first evidence that activation of P2X7 potentiates Wnt/β-catenin signaling. Stimulation of the ADP-sensitive P2Y 13 receptor has also been shown by others to promote β-catenin nuclear localization in cerebellar granule neurons [26]. Given that transcripts for P2Y 13 are present in MC3T3-E1 cells and rodent calvarial osteoblasts [27], it is possible that P2Y 13 may also modulate canonical Wnt signaling in our system.…”

Section: P2x7 Potentiates the Wnt/β-catenin Pathwaysupporting

confidence: 61%

“…Stimulation of the ADP-sensitive P2Y 13 receptor has also been shown by others to promote β-catenin nuclear localization in cerebellar granule neurons [26]. Given that transcripts for P2Y 13 are present in MC3T3-E1 cells and rodent calvarial osteoblasts [27], it is possible that P2Y 13 may also modulate canonical Wnt signaling in our system. However, we found that low concentrations of ATP, UTP, and ADP did not potentiate β-catenin transcriptional activity in the presence or absence of Wnt3a.…”

Section: P2x7 Potentiates the Wnt/β-catenin Pathwaysupporting

confidence: 61%

“…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%

“…Additionally, P2X7 is required to initiate signaling following fluid shear stress in cultures of osteoblast-like and osteocyte-like cells [11]. In cerebellar granule neurons, stimulation of the P2X7 receptor leads to inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) [13]. However, it is not known whether P2X7 can inhibit GSK3β in osteoblasts and thereby elicit activation of β-catenin.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Grol

Brooks

Pereverzev

et al. 2016

Purinergic Signalling

View full text Add to dashboard Cite

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.

show abstract

Section: P2x7 Potentiates the Wnt/β-catenin Pathwaysupporting

confidence: 92%

Section: P2x7 Potentiates the Wnt/β-catenin Pathwaysupporting

confidence: 61%

Section: P2x7 Potentiates the Wnt/β-catenin Pathwaysupporting

confidence: 61%

Section: Activation Of P2x7 Increases Inhibitory Phosphorylation Of Gmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Grol

Brooks

Pereverzev

et al. 2016

Purinergic Signalling

View full text Add to dashboard Cite

show abstract

Mechanisms of protein kinase D activation in response to P2Y₂ and P2X7 receptors in primary astrocytes

Carrasquero

Delicado

Sánchez‐Ruiloba

et al. 2010

Glia

Self Cite

View full text Add to dashboard Cite

Protein kinase D (PKD) is a family of serine/threonine kinases that can be activated by many stimuli via protein kinase C in a variety of cells. This is the first report where PKD activation and localization is studied in glial cells. Herein, we demonstrate that P2Y(2) and P2X7 receptor stimulation of primary rat cerebellar astrocytes rapidly increases PKD1/2 phosphorylation and activity. P2Y(2) receptor response evokes a PKD1/2 activation that is dependent on a pertussis toxin-insensitive G protein, phospholipase C (PLC)-mediated generation of diacylglycerol, and protein kinase C. This mechanism is similar to the one described for other G-protein coupled receptors. In contrast, the way the ionotropic P2X7 receptor activates PKD1/2 is significantly different. Importantly, this response is not dependent on calcium entry, but depends on the activity of several phospholipases, including phosphoinositide-phospholipase C (PI-PLC), phosphatidylcholine-phospholipase C (PC-PLC) and also phospholipase D (PLD). Immunoblot and confocal microscopy analysis show that PKD1/2 activation by nucleotides is transient. The active kinase first moves to and concentrates in certain plasma membrane domains. Then, phosphorylated-PKD1/2 translocates to intracellular vesicles, where it remains active. All together, our results open the perspective of PKD1/2 being involved in many physiological functions where nucleotides play important roles not only in astrocytes but in other cell types bearing these receptors.

show abstract

Paracrine Stimulation of P2x7 Receptor by Atp Activates a Proliferative Pathway in Ovarian Carcinoma Cells

et al. 2014

View full text Add to dashboard Cite

P2X7 is a purinergic receptor-channel; its activation by ATP elicits a broad set of cellular actions, from apoptosis to signals for survival. Here, P2X7 expression and function was studied in human ovarian carcinoma (OCA) cells, and biopsies from non-cancerous and cancer patients were analyzed by immunohistochemistry. Ovarian surface epithelium in healthy tissue expressed P2X7 at a high level that was maintained throughout the cancer. The cell lines SKOV-3 and CAOV-3 were used to investigate P2X7 functions in OCA. In SKOV-3 cells, selective stimulation of P2X7 by 2'(3')-O-(4-benzoylbenzoyl) adenosine-5'-triphosphate (BzATP) induced a dose-dependent increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) but not cell death. Instead, BzATP increased the levels of phosphorylated ERK and AKT (pERK and pAKT), with an EC(50) of 44 ± 2 and 1.27 ± 0.5 μM, respectively; 10 μM BzATP evoked a maximum effect within 15 min that lasted for 120 min. Interestingly, basal levels of pERK and pAKT were decreased in the presence of apyrase in the medium, strongly suggesting an endogenous, ATP-mediated phenomenon. Accordingly: (i) mechanically stimulated cells generated a [Ca(2+)](i) increase that was abolished by apyrase; (ii) apyrase induced a decrease in culture viability, as measured by the MTS assay for mitochondrial activity; and (iii) incubation with 10 μM AZ10606120, a specific P2X7 antagonist and transfection with the dominant negative P2X7 mutant E496A, both reduced cell viability to 70.1 ± 8.9% and to 76.5 ± 5%, respectively, of control cultures. These observations suggested that P2X7 activity was auto-induced through ATP efflux; this increased pERK and pAKT levels that generated a positive feedback on cell viability.

show abstract

P2X7 Nucleotide Receptor is Coupled to GSK-3 Inhibition and Neuroprotection in Cerebellar Granule Neurons

Cited by 48 publications

References 66 publications

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

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

Mechanisms of protein kinase D activation in response to P2Y₂ and P2X7 receptors in primary astrocytes

Paracrine Stimulation of P2x7 Receptor by Atp Activates a Proliferative Pathway in Ovarian Carcinoma Cells

Contact Info

Product

Resources

About

P2X7 Nucleotide Receptor is Coupled to GSK-3 Inhibition and Neuroprotection in Cerebellar Granule Neurons

Cited by 48 publications

References 66 publications

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

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

Mechanisms of protein kinase D activation in response to P2Y2 and P2X7 receptors in primary astrocytes

Paracrine Stimulation of P2x7 Receptor by Atp Activates a Proliferative Pathway in Ovarian Carcinoma Cells

Contact Info

Product

Resources

About

Mechanisms of protein kinase D activation in response to P2Y₂ and P2X7 receptors in primary astrocytes