mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

Liberto, Valentina Di; Mudò, Giuseppa; Belluardo, Natale

doi:10.1016/j.neuropharm.2011.05.006

Cited by 25 publications

(13 citation statements)

References 62 publications

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“…Our data suggest that activation of GSK-3β mediated only the trafficking of GluA2 but probably not that of GluA1 because GSK-3β inhibitor itself also downregulates the expression of GluA1, in agreement with a previous study [42]. Moreover, LY37 significantly increased phosphorylation of ERK1/2 but not the total protein level of ERK1/2, indicating that ERK1/2 is also directly regulated by posttranslational modification of phosphorylation, consistent with recent studies [44], [45], [92]. Furthermore, application of the ERK1/2 upstream MEK inhibitor PD98059, which is very effective in reducing p-ERK1 and p-ERK2 [93], blocked the increase of phosphorylation of ERK1/2 and completely blocked the LY37-induced increases in surface protein levels of GluA1 and GluA2.…”

Section: Discussionsupporting

confidence: 93%

Group II Metabotropic Glutamate Receptor Agonist LY379268 Regulates AMPA Receptor Trafficking in Prefrontal Cortical Neurons

Wang

Snyder

et al. 2013

PLoS ONE

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Group II metabotropic glutamate receptor (mGluR) agonists have emerged as potential treatment drugs for schizophrenia and other neurological disorders, whereas the mechanisms involved remain elusive. Here we examined the effects of LY379268 (LY37) on the expression and trafficking of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits GluA1 and GluA2 in prefrontal neurons. We show that LY37 significantly increased the surface and total expression of both GluA1 and GluA2 subunits in cultured prefrontal neurons and in vivo. This effect was mimicked by the selective mGluR2 agonist LY395756 and was blocked by mGluR2/3 antagonist LY341495. Moreover, we found that both GluA1 and GluA2 subunits were colocalized with PSD95 but not synapsin I, suggesting a postsynaptic localization. Consistently, treatment with LY37 significantly increased the amplitude, but not frequency, of miniature excitatory postsynaptic currents. Further, actinomycin-D blocked LY37's effects, suggesting a transcriptional regulation. In addition, application of glycogen synthase kinase-3beta (GSK-3β) inhibitor completely blocked LY37's effect on GluA2 surface expression, whereas GSK-3β inhibitor itself induced decreases in the surface and total protein levels of GluA1, but not GluA2 subunits. This suggests that GSK-3β differentially mediates GluA1 and GluA2 trafficking. Further, LY37 significantly increased the phosphorylation, but not total protein, of extracellular signal-regulated kinase 1/2 (ERK1/2). Neither ERK1/2 inhibitor PD98059 alone nor PD98059 combined with LY37 treatment induced changes in GluA1 or GluA2 surface expression or total protein levels. Our data thus suggest that mGluR2/3 agonist regulates postsynaptic AMPA receptors by affecting the synaptic trafficking of both GluA1 and GluA2 subunits and that the regulation is likely through ERK1/2 signaling in GluA1 and/or both ERK1/2 and GSK-3β signaling pathways in the GluA2 subunit.

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Section: Discussionsupporting

confidence: 93%

Group II Metabotropic Glutamate Receptor Agonist LY379268 Regulates AMPA Receptor Trafficking in Prefrontal Cortical Neurons

Wang

Snyder

et al. 2013

PLoS ONE

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“…Samples were sonicated (30 pulsations/min), quantified by the Lowry method (Lowry et al 1951), and stored at −80°C. Western blotting was performed as previously described (Di Liberto et al 2011). Protein samples (50 μg per lane) and molecular weight marker (161-0375 BIO-RAD) were run on polyacrylamide gel and electrophoretically transferred onto nitrocellulose membrane (RPN303E, Hybond-C-extra, GE Healthcare Europe GmbH).…”

Section: Cortisol Levelsmentioning

confidence: 99%

Anxiolytic effects of muscarinic acetylcholine receptors agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex

et al. 2016

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Rationale In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. Objectives Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. Methods The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2 mg/kg Oxo, and unstressed group treated with Oxo. After 21 days of CRS, the groups were treated for 10 days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/ dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels. Results Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex Conclusions The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex.

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“…While the role of GDNF in the neuronal and SSC niches is established, we know little about how this factor is regulated. In the brain, GDNF production by glial cells is enhanced by agonists of metabotropic glutamate receptors [23,24]. In the mouse testis, GDNF expression by Sertoli and peritubular cells might depend on levels of gonadotropic pituitary hormones (LH and FSH) and testosterone, but reports are conflicting and additional data will be necessary to fully understand the mechanisms of GDNF production [22,[25][26][27].…”

Section: Introductionmentioning

confidence: 99%

The NOTCH Ligand JAG1 Regulates GDNF Expression in Sertoli Cells

Garcia

Parekh

Gandhi

et al. 2017

Stem Cells and Development

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In the seminiferous epithelium of the testis, Sertoli cells are key niche cells directing proliferation and differentiation of spermatogonial stem cells (SSCs) into spermatozoa. Sertoli cells produce glial cell line-derived neurotrophic factor (GDNF), which is essential for SSC self-renewal and progenitor expansion. While the role of GDNF in the testis stem cell niche is established, little is known about how this factor is regulated. Our previous studies on NOTCH activity in Sertoli cells demonstrated a role of this pathway in limiting stem/progenitor cell numbers, thus ultimately downregulating sperm cell output. In this study we demonstrate through a double-mutant mouse model that NOTCH signaling in Sertoli cells functions solely through the canonical pathway. Further, we demonstrate through Dual luciferase assay and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) analysis that the NOTCH targets HES1 and HEY1, which are transcriptional repressors, directly downregulate GDNF expression by binding to the Gdnf promoter, thus antagonizing the effects of FSH/cAMP. Finally, we demonstrate that testicular stem/progenitors cells are activating NOTCH signaling in Sertoli cells in vivo and in vitro through the NOTCH ligand JAG1 at their surface, indicating that these cells may ensure their own homeostasis through negative feedback regulation.

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mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

Cited by 25 publications

References 62 publications

Group II Metabotropic Glutamate Receptor Agonist LY379268 Regulates AMPA Receptor Trafficking in Prefrontal Cortical Neurons

Group II Metabotropic Glutamate Receptor Agonist LY379268 Regulates AMPA Receptor Trafficking in Prefrontal Cortical Neurons

Anxiolytic effects of muscarinic acetylcholine receptors agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex

The NOTCH Ligand JAG1 Regulates GDNF Expression in Sertoli Cells

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