Down-regulation of Homer1b/c attenuates glutamate-mediated excitotoxicity through endoplasmic reticulum and mitochondria pathways in rat cortical neurons

Chen, Tao; Fei, Fei; Jiang, Xiaofan; Zhang, Lei; Qu, Yan; Huo, Kai; Zhou, Fei

doi:10.1016/j.freeradbiomed.2011.10.451

Cited by 114 publications

(84 citation statements)

References 51 publications

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“…mGluRs form a family of eight subtypes, mGluR1 to mGluR8, subdivided into three groups (group I, II and III) on the basis of their amino acid sequence, G-protein coupling and pharmacological profile. Activation of group I mGluRs, including mGluR1 and mGluR5, leads to the hydrolysis of phosphatidylinositol-4,5 -bisphosphate (InsP3) and diacylglycerol (DAG) [7,8]. These receptors have been implicated in diverse neurological pathology, including brain trauma, cerebral ischemia, chronic central pain, amyotrophic lateral sclerosis (ALS), Fragile X syndrome as well as neurodegenerative diseases [9,10,11,12,13].…”

Section: Introductionmentioning

confidence: 99%

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

Zhang

Yuan

et al. 2015

Cell Physiol Biochem

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Background: Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that mediate neuronal excitability and synaptic plasticity in the central nervous system, and emerging evidence suggests a role of mGluRs in the biology of cancer. Previous studies showed that mGluR1 was a potential therapeutic target for the treatment of breast cancer and melanoma, but its role in human glioma has not been determined. Methods: In the present study, we investigated the effects of mGluR1 inhibition in human glioma U87 cells using specific targeted small interfering RNA (siRNA) or selective antagonists Riluzole and BAY36-7620. The anti-cancer effects of mGluR1 inhibition were measured by cell viability, lactate dehydrogenase (LDH) release, TUNEL staining, cell cycle assay, cell invasion and migration assays in vitro, and also examined in a U87 xenograft model in vivo. Results: Inhibition of mGluR1 significantly decreased the cell viability but increased the LDH release in a dose-dependent fashion in U87 cells. These effects were accompanied with the induction of caspase-dependent apoptosis and G0/G1 cell cycle arrest. In addition, the results of Matrigel invasion and cell tracking assays showed that inhibition of mGluR1 apparently attenuated cell invasion and migration in U87 cells. All these anti-cancer effects were ablated by the mGluR1 agonist L-quisqualic acid. The results of western blot analysis showed that mGluR1 inhibition overtly decreased the phosphorylation of PI3K, Akt, mTOR and P70S6K, indicating the mitigated activation of PI3K/Akt/mTOR pathway. Moreover, the anti-tumor activity of mGluR1 inhibition in vivo was also demonstrated in a U87 xenograft glioma model in athymic nude mice. Conclusion: The remarkable efficiency of mGluR1 inhibition to induce cell death in U87 cells may find therapeutic application for the treatment of glioma patients.

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Section: Introductionmentioning

confidence: 99%

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

Zhang

Yuan

et al. 2015

Cell Physiol Biochem

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“…Specifically, we have previously described loss of Vesl-1L/Homer-1c as biomarker for synaptic changes after injury in the retina (Kaja et al 2003), and experimental down-regulation of Homer1b/c has been shown to attenuate glutamate-mediated toxicity in cortical neurons in vitro (Chen et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Homer-1a immediate early gene expression correlates with better cognitive performance in aging

Kaja

Sumien

Borden

et al. 2012

AGE

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The molecular mechanisms underlying cognitive decline during healthy aging remain largely unknown. Utilizing aged wild-type C57BL/6 mice as a model for normal aging, we tested the hypothesis that cognitive performance, memory, and learning as assessed in established behavioral testing paradigms are correlated with the differential expression of isoforms of the Homer family of synaptic scaffolding proteins. Here we describe a loss of cognitive and motor function that occurs when Homer-1a/Vesl-1S protein levels drop during aging. Our data describe a novel mechanism of age-related synaptic changes contributing to loss of biological function, spatial learning, and memory formation as well as motor coordination, with the dominant negative uncoupler of synaptic protein clustering, Homer-1a/Vesl-1S, as a potential target for the prophylaxis and treatment of age-related cognitive decline.

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“…Then, the cells were resuspended in Neurobasal medium (Gibco, Paisley, UK) containing 2% B-27, 0.5 mM Lglutamine, and 1% penicillin/streptomycin and seeded at a density of 5 × 10 4 cells/cm. 2 Prior to seeding, 24-and 96-well plates were coated with Poly L-Lysine (PLL, MW = 70,000-150,000 g/mol; 10 µg/ml, Sigma, St Louis, MO) at 37°C overnight. Isolated neurons cultured at humidified 37°C with 5% CO 2 incubator.…”

Section: Primary Cultures Of Cortical Neurons and Glutamate Exposurementioning

confidence: 99%

“…1 Neuronal dysfunction and cell death are mediated by different mechanisms such as the production of reactive oxygen species, releasing neuronal zinc, poly (ADPribose) polymerase-1 activation, mitochondrial dysfunction, and overstimulation of enzymes such as calpains and other proteases, phospholipases, and endonucleases. [1][2][3][4][5] Oxidative glutamate toxicity is another mechanism in which cystine/glutamate transporters are inhibited by excessive glutamate concentration. Furthermore, the cystine uptake is inhibited which decreases intracellular glutathione levels and finally lead to neuronal oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

“…6 Glutamate-induced excitotoxicity has been reported in both acute injuries such as ischemic stroke, and chronic brain disorders such as Alzheimer's and Parkinson's diseases. 2 Studies showed that glutamate receptors antagonists are not efficient to protect neurons against excitotoxicity and hence it is necessary to find new approaches to limiting glutamate-induced toxicity. 5 Adult mammalian brain contains neural stem cells (NSCs) that give rise into new neurons and glial cells throughout life.…”

Section: Introductionmentioning

confidence: 99%

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Paracrine Neuroprotective Effects of Neural Stem Cells on Glutamate-Induced Cortical Neuronal Cell Excitotoxicity

et al. 2015

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Down-regulation of Homer1b/c attenuates glutamate-mediated excitotoxicity through endoplasmic reticulum and mitochondria pathways in rat cortical neurons

Cited by 114 publications

References 51 publications

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

Homer-1a immediate early gene expression correlates with better cognitive performance in aging

Paracrine Neuroprotective Effects of Neural Stem Cells on Glutamate-Induced Cortical Neuronal Cell Excitotoxicity

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