Adenosine-mediated activation of Akt/protein kinase B in the rat hippocampus in vitro and in vivo

Gervitz, Leon; Nalbant, Demet; Williams, Simon C.; Fowler, John C.

doi:10.1016/s0304-3940(02)00495-0

Cited by 22 publications

(19 citation statements)

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“…Akt regulates cell proliferation and a plethora of biological processes (also see Discussion) by the phosphorylation of downstream targets such as GSK3β, the mammalian Target of Rapamycin (mTOR), caspase 9, forkhead transcription factor, IĸB Kinase, and p21 cip1 /p27 kip1 [27, 28]. We hypothesized that extracellular ATP and adenosine would induce Akt activation in U138-MG glioma cells, as the activation of adenosine A1 receptors leads to the activation of Akt in rat hippocampus in vitro and in vivo [29], and the stimulation of P2Y and P2X receptors is linked to Akt phosphorylation in renal mesangial cells and rat cortical astrocytes [21, 30]. …”

Section: Resultsmentioning

confidence: 99%

“…Akt is a 57-kD Ser/Thr kinase involved in a variety of biological effects, such as cell survival, cell cycle and apoptosis regulation, protein synthesis, differentiation, and glucose metabolism [55, 56]. The activation of the PI3K/Akt pathway is linked to the A3-type adenosine receptor in basophilic leukemia (RBL)-2H3 mast-like cells [57]and Chinese hamster ovary cells [58]and to adenosine A1 receptors in rat hippocampus [29]. We have shown that P2X and P2Y receptors are linked to the activation of the PI3K/Akt pathway in rat cortical astrocytes [21].…”

Section: Discussionmentioning

confidence: 99%

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ERK, PKC and PI3K/Akt Pathways Mediate Extracellular ATP and Adenosine-Induced Proliferation of U138-MG Human Glioma Cell Line

Jacques-Silva¹,

Bernardi²,

Rodnight³

et al. 2004

Oncology

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Objective: Extracellular nucleotides and nucleosides induce proliferation in a set of human glioma cell lines. In this study we investigate the signal transduction pathways involved in ATP and adenosine-mediated proliferation in U138-MG human glioma cells. Methods: Cell proliferation was accessed through [³H]thymidine incorporation, cell counting and flow cytometry. Protein phosphorylation was detected through Western blotting. Results: ATP or adenosine (100 µM) induced extracellular signal-regulated protein kinase (ERK), Akt and GSK3β phosphorylation. The increase in [³H]thymidine incorporation induced by ATP or adenosine was decreased when cells were incubated with LY 294002 (by ±90%), GF 109203X (by ±76%) or PD 098059 (by ±63%). The increase in cell numbers with ATP or adenosine was less after a 48-hour treatment of cells with ATP or adenosine plus GF 109203X (by ±66%) or LY 294002 (by ±83%). Percentage of cells in S phase was decreased in cells treated with LY 294002 plus ATP when compared to ATP- treated cells. Conclusion: Stimulation of purinergic receptors in U138-MG cells leads to cell proliferation mediated by PI3K/Akt, ERK and PKC signaling. It may be clinically important for pharmacological intervention in gliomas to associate purinergic receptor antagonists and signal transduction pathways blockers.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ERK, PKC and PI3K/Akt Pathways Mediate Extracellular ATP and Adenosine-Induced Proliferation of U138-MG Human Glioma Cell Line

Jacques-Silva¹,

Bernardi²,

Rodnight³

et al. 2004

Oncology

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“…ERK1/2 activation can also produce neuroprotection (Xia et al, 1995). Both intracellular pathways are activated by A 1 receptor stimulation in non-neuronal (Germack and Dickenson, 2000) and neuronal cells (Angulo et al, 2003) and in brain tissue (Gervitz et al, 2002). Activation of mGlu2/3 receptors can also stimulate Akt/PKB and ERK1/2 in astrocytes and in brain tissue .…”

Section: A 1 and Mglu3 Receptor Antiapoptotic Effect In Astrocytes 1377mentioning

confidence: 99%

Molecular Signalling Mediating the Protective Effect of A₁Adenosine and mGlu3 Metabotropic Glutamate Receptor Activation against Apoptosis by Oxygen/Glucose Deprivation in Cultured Astrocytes

Ciccarelli¹,

D’Alimonte²,

Ballerini³

et al. 2007

Mol Pharmacol

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Astrocyte death may occur in neurodegenerative disorders and complicates the outcome of brain ischemia, a condition associated with high extracellular levels of adenosine and glutamate. We show that pharmacological activation of A 1 adenosine and mGlu3 metabotropic glutamate receptors with N 6 -chlorocyclopentyladenosine (CCPA) and (Ϫ)2-oxa-4-aminocyclo-[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), respectively, protects cultured astrocytes against apoptosis induced by a 3-h exposure to oxygen/glucose deprivation (OGD). Protection by CCPA and LY379268 was less than additive and was abrogated by receptor blockade with selective competitive antagonists or pertussis toxin. Both in control astrocytes and in astrocytes exposed to OGD, CCPA and LY379268 induced a rapid activation of the phosphatidylinositol-3-kinase (PI3K) and extracellular signal-regulated kinases 1 and 2 (ERK1/2)/mitogen-activated protein kinase (MAPK) pathways, which are known to support cell survival. In cultures exposed to OGD, CCPA and LY379268 reduced the activation of c-Jun N-terminal kinase and p38/MAPK, reduced the levels of the proapoptotic protein Bad, increased the levels of the antiapoptotic protein Bcl-X L , and were highly protective against apoptotic death, as shown by nuclear 4Ј-6-diamidino-2-phenylindole staining and measurements of caspase-3 activity. All of these effects were attenuated by treatment with 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), which inhibit the MAPK and the PI3K pathways, respectively. These data suggest that pharmacological activation of A 1 and mGlu3 receptors protects astrocytes against hypoxic/ischemic damage by stimulating the PI3K and ERK1/2 MAPK pathways.Astrocytes, the most abundant glial cell types in the brain, provide metabolic and trophic support to neurons by several mechanisms that include the clearance of ions and environmental toxins, the supply of energy substrates, and the production of trophic factors, and modulate synaptic activity (Volterra and Meldolesi, 2005). Impairments in these functions critically affect neuronal survival.Recent studies have shown that ischemic and inflammatory insults induce astrocyte apoptotic death, and this contributes to the pathophysiology of short-and long-term neurodegenerative disorders (Takuma et al., 2004). Apoptotic astrocytes are found in Alzheimer's disease (Kobayashi et al., ABBREVIATIONS: CCPA, N 6 -chlorocyclopentyladenosine; ASK1, apoptosis-signal-regulating kinase 1; DAPI, 4Ј-6-diamidino-2-phenylindole; DMEM, Dulbecco's modified Eagle's medium; DPCPX, 1,3-dipropyl-8-cyclopentyl xanthine; ERK1/2, extracellular signal-regulated kinases 1 and 2; HRP, horseradish peroxidase; JNK, c-Jun N-terminal kinase; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; LY341495, (2S,1ЈS,2ЈS)-2(9-xanthylmethyl)-2-(2Ј-carboxycyclo-propyl)glycine; LY379268, (Ϫ)2-oxa-4-aminocyclo-[3.1.0] hexane-4,6-dicarboxylic acid; MAPK, mitogen-activated p...

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“…Serine/threonine protein kinase B (PKB, also called Akt) is part of an endogenous neuroprotection pathway in both necrotic and apoptotic models of neuronal cell death [4] , and an A 1 R agonist has been reported to induce Akt phosphorylation in DDT 1 MF-2 [5] and the rat hippocampus [6] . However, the signaling mediators of the A 1 R-induced Akt activation pathway have not yet been identified in the neurons.…”

Section: Introductionmentioning

confidence: 99%

Adenosine A1 receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro

et al. 2009

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Aim: To understand the mechanism of the transactivation of the epidermal growth factor receptor (EGFR) mediated by the adenosine A 1 receptor (A 1 R). Methods: Primary cultured rat cortical neurons subjected to oxygen-glucose deprivation (OGD) and HEK293/A 1 R cells were treated with the A 1 R-specific agonist N 6 -cyclopentyladenosine (CPA). Phospho-EGFR, Akt, and ERK1/2 were observed by Western blot. An interaction between EGFR and A 1 R was detected using immunoprecipitation and immunocytochemistry. Results: The A 1 R agonist CPA causes protein kinase B (Akt) activation and protects primary cortical neurons from oxygen-glucose deprivation (OGD) insult. A 1 R and EGFR co-localize in the membranes of neurons and form an immunocomplex. A 1 R stimulation induces significant EGFR phosphorylation via a PI3K and Src kinase signaling pathway; this stimulation provides a neuroprotective effect in cortical neurons. CPA leads to sustained phosphorylation of extracellularly regulated kinases 1 and 2 (ERK1/2) in cortical neurons, but only to transient phosphorylation in HEK 293/A 1 R cells. The response to the A 1 R agonist is mediated primarily through EGFR transactivation that is dependent on pertussis toxin (PTX)-sensitive G i protein and metalloproteases in HEK 293/A 1 R. Conclusion: A 1 R-mediated EGFR transactivation confers a neuroprotective effect in primary cortical neurons. PI3 kinase and Src kinase play pivotal roles in this response.

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Adenosine-mediated activation of Akt/protein kinase B in the rat hippocampus in vitro and in vivo

Cited by 22 publications

References 18 publications

ERK, PKC and PI3K/Akt Pathways Mediate Extracellular ATP and Adenosine-Induced Proliferation of U138-MG Human Glioma Cell Line

ERK, PKC and PI3K/Akt Pathways Mediate Extracellular ATP and Adenosine-Induced Proliferation of U138-MG Human Glioma Cell Line

Molecular Signalling Mediating the Protective Effect of A₁Adenosine and mGlu3 Metabotropic Glutamate Receptor Activation against Apoptosis by Oxygen/Glucose Deprivation in Cultured Astrocytes

Adenosine A1 receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro

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Adenosine-mediated activation of Akt/protein kinase B in the rat hippocampus in vitro and in vivo

Cited by 22 publications

References 18 publications

ERK, PKC and PI3K/Akt Pathways Mediate Extracellular ATP and Adenosine-Induced Proliferation of U138-MG Human Glioma Cell Line

ERK, PKC and PI3K/Akt Pathways Mediate Extracellular ATP and Adenosine-Induced Proliferation of U138-MG Human Glioma Cell Line

Molecular Signalling Mediating the Protective Effect of A1Adenosine and mGlu3 Metabotropic Glutamate Receptor Activation against Apoptosis by Oxygen/Glucose Deprivation in Cultured Astrocytes

Adenosine A1 receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro

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Molecular Signalling Mediating the Protective Effect of A₁Adenosine and mGlu3 Metabotropic Glutamate Receptor Activation against Apoptosis by Oxygen/Glucose Deprivation in Cultured Astrocytes