Astrocytes in culture express the full-length Trk-B receptor and respond to brain derived neurotrophic factor by changing intracellular calcium levels: effect of ethanol exposure in rats

Climent, Eva; Sancho‐Tello, María; Miñana, Rosa; Barettino, Domingo; Guerri, Consuelo

doi:10.1016/s0304-3940(00)01207-6

Cited by 63 publications

(55 citation statements)

References 18 publications

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“…We found that BDNF induced a sustained increase in TrkB-T1 receptors are predominantly expressed in rat astrocytes (33), while the expression of TrkB-FL receptors is up-regulated after brain injury (55). Although the physiological significance of truncated TrkB receptors is still unknown (38,56), several studies support the importance of TrkB-T1 receptors in the CNS.…”

Section: Discussionmentioning

confidence: 79%

Brain-Derived Neurotrophic Factor Induces Sustained Elevation of Intracellular Ca2+ in Rodent Microglia

Mizoguchi

Monji

Kato

et al. 2009

The Journal of Immunology

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Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, NO, and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. In this study, we observed that BDNF induced a sustained increase in [Ca2+]i through binding with the truncated tropomyosin-related kinase B receptor, resulting in activation of the PLC pathway and store-operated calcium entry in rodent microglial cells. RT-PCR and immunocytochemical techniques revealed that truncated tropomyosin-related kinase B-T1 receptors were highly expressed in rodent microglial cells. Sustained activation of store-operated calcium entry occurred after brief BDNF application and contributed to the maintenance of sustained [Ca2+]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, pretreatment of BDNF suppressed the IFN-γ-induced increase in [Ca2+]i, along with a rise in basal levels of [Ca2+]i in rodent microglial cells. We show direct evidence that rodent microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses, and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 79%

Brain-Derived Neurotrophic Factor Induces Sustained Elevation of Intracellular Ca2+ in Rodent Microglia

Mizoguchi

Monji

Kato

et al. 2009

The Journal of Immunology

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“…Intracellular Ca 2ϩ modulates the proliferative effects of EGF (16,39,40), and complex Ca 2ϩ oscillations are associated with human astrocytoma cell migration (25,41,42 , and activity of store-operated calcium channels. Here, we show that extracellular HSP90␣ transiently increases cytosolic [Ca 2ϩ ] in glioblastoma U87 cells and converts calcium response induced by EGF from a transient to an oscillatory pattern.…”

Section: Discussionmentioning

confidence: 99%

“…The HSP90␣/HER-2 interaction favors HER-2 heterodimerization with ErbB3 and signal transduction pathways via MAPK and PI3K-Akt, leading to actin rearrangement and cell motility (7). EGFR (ErbB1, or HER1) is overexpressed in 60% of multiform glioblastomas (13,14) and promotes invasion, proliferation, and metastasis (15)(16)(17) in response to several ligands known as EGF-related peptide growth factors (18). Binding of these ligands to the extracellular domain of EGFR leads to the formation of homo-and heterodimers, which triggers autophosphorylation of specific tyrosine residues within the cytoplasmic domain of EGFR, inducing signaling cascades.…”

mentioning

confidence: 99%

Transactivation of the Epidermal Growth Factor Receptor by Heat Shock Protein 90 via Toll-like Receptor 4 Contributes to the Migration of Glioblastoma Cells

Thüringer

Hammann

Benikhlef

et al. 2011

Journal of Biological Chemistry

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Extracellular heat shock protein HSP90␣ was reported to participate in tumor cell growth, invasion, and metastasis formation through poorly understood signaling pathways. Herein, we show that extracellular HSP90␣ favors cell migration of glioblastoma U87 cells. More specifically, externally applied HSP90␣ rapidly induced endocytosis of EGFR. This response was accompanied by a transient increase in cytosolic Ca 2؉ appearing after 1-3 min of treatment. In the presence of EGF, U87 cells showed HSP90␣-induced Ca 2؉ oscillations, which were reduced by the ATP/ADPase, apyrase, and inhibited by the purinergic P 2 inhibitor, suramin, suggesting that ATP release is requested. Disruption of lipid rafts with methyl ␤-cyclodextrin impaired the Ca 2؉ rise induced by extracellular HSP90␣ combined with EGF. Specific inhibition of TLR4 expression by blocking antibodies suppressed extracellular HSP90␣-induced Ca 2؉ signaling and the associated cell migration. HSPs are known to bind lipopolysaccharides (LPSs). Preincubating cells with Polymyxin B, a potent LPS inhibitor, partially abrogated the effects of HSP90␣ without affecting Ca 2؉ oscillations observed with EGF. Extracellular HSP90␣ induced EGFR phosphorylation at Tyr-1068, and this event was prevented by both the protein kinase C␦ inhibitor, rottlerin, and the c-Src inhibitor, PP2. Altogether, our results suggest that extracellular HSP90␣ transactivates EGFR/ErbB1 through TLR4 and a PKC␦/c-Src pathway, which induces ATP release and cytosolic Ca 2؉ increase and finally favors cell migration. This mechanism could account for the deleterious effects of HSPs on high grade glioma when released into the tumor cell microenvironment.Glioma ranges from slowly growing low grade tumors to rapidly growing high grade tumors, including anaplastic astrocytoma and glioblastoma (1, 2). High grade gliomas include anaplastic tumor cells, necrotic foci, and rich vascularity, due largely to the aberrant expression of angiogenic factors by tumor cells (3). Tumor cells are highly proliferative and invasive within the brain. Despite the development of various treatments, the life expectancy of patients remains poor (4).One of the molecules that could contribute to invasion is the stress or heat shock protein 90 (HSP90). In several tumor types, cell surface expression of HSP90 correlates with metastatic potential (5), and its inhibition with antibodies (6, 7) or with cell-impermeable inhibitors (8) reduces cell migration in vitro. Of the two HSP90 isoforms, only HSP90␣ has been described extracellularly, which argues against cell lysis as the source of extracellular HSP90 (8). The metalloprotease MMP-2 can be associated with extracellular HSP90␣ (8), which is favored by acetylation of the stress protein (9). Surface HSP90␣ also participates in extracellular matrix proteininduced c-Src/integrin association and reorganization of the actin cytoskeleton (10). The cell-impermeable inhibitor of HSP90, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG)-N-oxide, displays anti-invasive and anti-meta...

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“…BDNF could have protective effects on neurons and on astrocytes themselves, the latter being an issue that has not been thoroughly investigated. BDNF stimulates S100b expression in mouse astrocytes (Djalali et al 2005), and it increases intracellular calcium levels of rat astrocytes (Climent et al 2000), but much study is still needed to fully understand the effects of BDNF in astroglial cells.…”

Section: Mechanisms Of Mc4r-mediated Effectsmentioning

confidence: 99%

Astrocytes: new targets of melanocortin 4 receptor actions

Caruso¹,

Carniglia²,

Durand³

et al. 2013

Journal of Molecular Endocrinology

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Astrocytes exert a wide variety of functions with paramount importance in brain physiology. After injury or infection, astrocytes become reactive and they respond by producing a variety of inflammatory mediators that help maintain brain homeostasis. Loss of astrocyte functions as well as their excessive activation can contribute to disease processes; thus, it is important to modulate reactive astrocyte response. Melanocortins are peptides with well-recognized anti-inflammatory and neuroprotective activity. Although melanocortin efficacy was shown in systemic models of inflammatory disease, mechanisms involved in their effects have not yet been fully elucidated. Central anti-inflammatory effects of melanocortins and their mechanisms are even less well known, and, in particular, the effects of melanocortins in glial cells are poorly understood. Of the five known melanocortin receptors (MCRs), only subtype 4 is present in astrocytes. MC4R has been shown to mediate melanocortin effects on energy homeostasis, reproduction, inflammation, and neuroprotection and, recently, to modulate astrocyte functions. In this review, we will describe MC4R involvement in anti-inflammatory, anorexigenic, and anti-apoptotic effects of melanocortins in the brain. We will highlight MC4R action in astrocytes and discuss their possible mechanisms of action. Melanocortin effects on astrocytes provide a new means of treating inflammation, obesity, and neurodegeneration, making them attractive targets for therapeutic interventions in the CNS.

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Astrocytes in culture express the full-length Trk-B receptor and respond to brain derived neurotrophic factor by changing intracellular calcium levels: effect of ethanol exposure in rats

Cited by 63 publications

References 18 publications

Brain-Derived Neurotrophic Factor Induces Sustained Elevation of Intracellular Ca2+ in Rodent Microglia

Brain-Derived Neurotrophic Factor Induces Sustained Elevation of Intracellular Ca2+ in Rodent Microglia

Transactivation of the Epidermal Growth Factor Receptor by Heat Shock Protein 90 via Toll-like Receptor 4 Contributes to the Migration of Glioblastoma Cells

Astrocytes: new targets of melanocortin 4 receptor actions

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