ArticleGlia2011
Disruption of astrocytic glutamine turnover by manganese is mediated by the protein kinase C pathway.
Article in Glia, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 55 citations in OpenAlex.
- Protein Kinase C-delta (PKCδ) in Neurodegeneration and Cerebral Ischemia: Molecular Mechanisms and Therapeutic Implications.Cell biochemistry and biophysics · 2026Review
- Consensus of Expert Opinion for the Diagnosis and Management of Hypermanganesaemia With Dystonia 1 and 2.Journal of inherited metabolic disease · 2025Article
- Stem Cell Therapy and Thiamine Deficiency-Induced Brain Damage.Neurochemical research · 2024Review
- Manganese in autism spectrum disorder and attention deficit hyperactivity disorder: The state of the art.Current research in toxicology · 2024Review
- The Role of Oxidative Stress in Manganese Neurotoxicity: A Literature Review Focused on Contributions Made by Professor Michael Aschner.Biomolecules · 2023Review
- Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response.iScience · 2023Article
- Astrocyte Reaction to Catechol-Induced Cytotoxicity Relies on the Contact with Microglia Before Isolation.Neurotoxicity research · 2022Article
- The Role of Nrf2 Transcription Factor and Sp1-Nrf2 Protein Complex in Glutamine Transporter SN1 Regulation in Mouse Cortical Astrocytes Exposed to Ammonia.International journal of molecular sciences · 2021Article
- Mechanisms of Neurodegeneration in Various Forms of Parkinsonism-Similarities and Differences.Cells · 2021Review
- Critical Involvement of Glial Cells in Manganese Neurotoxicity.BioMed research international · 2021Review
- The impact of manganese on neurotransmitter systems.Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) · 2020Review
- Ubiquitylation and endocytosis of the human LAT1/SLC7A5 amino acid transporter.Scientific reports · 2019Article
- Role of Astrocytes in Manganese Neurotoxicity Revisited.Neurochemical research · 2019Review
- Environmental neurotoxicant-induced dopaminergic neurodegeneration: a potential link to impaired neuroinflammatory mechanisms.Pharmacology & therapeutics · 2019Review
- Silencing of Transcription Factor Sp1 Promotes SN1 Transporter Regulation by Ammonia in Mouse Cortical Astrocytes.International journal of molecular sciences · 2019Article
- PKC-Mediated Modulation of Astrocyte SNAT3 Glutamine Transporter Function at Synapses in Situ.International journal of molecular sciences · 2018Article
- Astrocytes in mouse models of tauopathies acquire early deficits and lose neurosupportive functions.Acta neuropathologica communications · 2017Article
- Manganese-Mediated Decrease in Levels of c-RET and Tyrosine Hydroxylase Expression In Vitro.Neurotoxicity research · 2017Article
- Manganese Control of Glutamate Transporters' Gene Expression.Advances in neurobiology · 2017Review
- "Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies".BMC pharmacology & toxicology · 2016Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Manganese (Mn) is a trace element essential for normal human development and is required for the proper functioning of a variety of physiological processes. Chronic exposure to Mn can cause manganism, a neurodegenerative disorder resembling idiopathic Parkinson's disease (PD). Mn(II) neurotoxicity is characterized by astrocytic impairment both in the expression and activity of glutamine (Gln) transporters. Because protein kinase C (PKC) activation leads to the downregulation of a number of neurotransmitter transporters and Mn(II) increases PKC activity, we hypothesized that the PKC signaling pathway contributes to the Mn(II)-mediated disruption of Gln turnover. Our results have shown that Mn exposure increases the phosphorylation of both the PKCα and PKCδ isoforms. PKC activity was also shown to be increased in response to Mn(II) treatment. Corroborating our earlier observations, Mn(II) also caused a decrease in Gln uptake. This effect was blocked by PKC inhibitors. Notably, PKC activation caused a decrease in Gln uptake mediated by systems ASC and N, but had no effect on the activities of systems A and L. Exposure to α-phorbol 12-myristate 13-acetate significantly decreased SNAT3 (system N) and ASCT2 (system ASC) protein levels. Additionally, a co-immunoprecipitation study demonstrated the association of SNAT3 and ASCT2 with the PKCδ isoform, and Western blotting revealed the Mn(II)-mediated activation of PKCδ by proteolytic cleavage. PKC activation was also found to increase SNAT3 and ubiquitin ligase Nedd4-2 binding and to induce hyperubiquitination. Taken together, these findings demonstrate that the Mn(II)-induced dysregulation of Gln homeostasis in astrocytes involves PKCδ signaling accompanied by an increase in ubiquitin-mediated proteolysis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.