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      Astrocytes Protect Neurons against Methylmercury via ATP/P2Y 1 Receptor-Mediated Pathways in Astrocytes

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          Abstract

          Methylmercury (MeHg) is a well known environmental pollutant that induces serious neuronal damage. Although MeHg readily crosses the blood-brain barrier, and should affect both neurons and glial cells, how it affects glia or neuron-to-glia interactions has received only limited attention. Here, we report that MeHg triggers ATP/P2Y 1 receptor signals in astrocytes, thereby protecting neurons against MeHg via interleukin-6 (IL-6)-mediated pathways. MeHg increased several mRNAs in astrocytes, among which IL-6 was the highest. For this, ATP/P2Y 1 receptor-mediated mechanisms were required because the IL-6 production was (i) inhibited by a P2Y 1 receptor antagonist, MRS2179, (ii) abolished in astrocytes obtained from P2Y 1 receptor-knockout mice, and (iii) mimicked by exogenously applied ATP. In addition, (iv) MeHg released ATP by exocytosis from astrocytes. As for the intracellular mechanisms responsible for IL-6 production, p38 MAP kinase was involved. MeHg-treated astrocyte-conditioned medium (ACM) showed neuro-protective effects against MeHg, which was blocked by anti-IL-6 antibody and was mimicked by the application of recombinant IL-6. As for the mechanism of neuro-protection by IL-6, an adenosine A 1 receptor-mediated pathway in neurons seems to be involved. Taken together, when astrocytes sense MeHg, they release ATP that autostimulates P2Y 1 receptors to upregulate IL-6, thereby leading to A 1 receptor-mediated neuro-protection against MeHg.

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          GLIA: listening and talking to the synapse.

          P G Haydon (2001)
          Glial cells are emerging from the background to become more prominent in our thinking about integration in the nervous system. Given that glial cells associated with synapses integrate neuronal inputs and can release transmitters that modulate synaptic activity, it is time to rethink our understanding of the wiring diagram of the nervous system. It is no longer appropriate to consider solely neuron-neuron connections; we also need to develop a view of the intricate web of active connections among glial cells, and between glia and neurons. Without such a view, it might be impossible to decode the language of the brain.
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            PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo.

            D Alessi, A Cuenda, P. Cohen … (1995)
            PD 098059 has been shown previously to inhibit the dephosphorylated form of mitogen-activated protein kinase kinase-1 (MAPKK1) and a mutant MAPKK1(S217E,S221E), which has low levels of constitutive activity (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 7686-7689). Here we report that PD 098059 does not inhibit Raf-activated MAPKK1 but that it prevents the activation of MAPKK1 by Raf or MEK kinase in vitro at concentrations (IC50 = 2-7 microM) similar to those concentrations that inhibit dephosphorylated MAPKK1 or MAPKK1(S217E,S221E). PD 098059 inhibited the activation of MAPKK2 by Raf with a much higher IC50 value (50 microM) and did not inhibit the phosphorylation of other Raf or MEK kinase substrates, indicating that it exerts its effect by binding to the inactive form of MAPKK1. PD 098059 also acts as a specific inhibitor of the activation of MAPKK in Swiss 3T3 cells, suppressing by 80-90% its activation by a variety of agonists. The high degree of specificity of PD 098059 in vitro and in vivo is indicated by its failure to inhibit 18 protein Ser/Thr kinases (including two other MAPKK homologues) in vitro by its failure to inhibit the in vivo activation of MAPKK and MAP kinase homologues that participate in stress and interleukin-1-stimulated kinase cascades in KB and PC12 cells, and by lack of inhibition of the activation of p70 S6 kinase by insulin or epidermal growth factor in Swiss 3T3 cells. PD 098059 (50 microM) inhibited the activation of p42MAPK and isoforms of MAP kinase-activated protein kinase-1 in Swiss 3T3 cells, but the extent of inhibition depended on how potently c-Raf and MAPKK were activated by any particular agonist and demonstrated the enormous amplification potential of this kinase cascade. PD 098059 not only failed to inhibit the activation of Raf by platelet-derived growth factor, serum, insulin, and phorbol esters in Swiss 3T3 cells but actually enhanced Raf activity. The rate of activation of Raf by platelet-derived growth factor was increased 3-fold, and the subsequent inactivation that occurred after 10 min was prevented. These results indicate that the activation of Raf is suppressed and that its inactivation is accelerated by a downstream component(s) of the MAP kinase pathway.
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              Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25.

              J Blasi, E Chapman, E. Link … (1993)
              Neurotransmitter release is potently blocked by a group of structurally related toxin proteins produced by Clostridium botulinum. Botulinum neurotoxin type B (BoNT/B) and tetanus toxin (TeTx) are zinc-dependent proteases that specifically cleave synaptobrevin (VAMP), a membrane protein of synaptic vesicles. Here we report that inhibition of transmitter release from synaptosomes caused by botulinum neurotoxin A (BoNT/A) is associated with the selective proteolysis of the synaptic protein SNAP-25. Furthermore, isolated or recombinant L chain of BoNT/A cleaves SNAP-25 in vitro. Cleavage occurred near the carboxyterminus and was sensitive to divalent cation chelators. In addition, a glutamate residue in the BoNT/A L chain, presumably required to stabilize a water molecule in the zinc-containing catalytic centre, was required for proteolytic activity. These findings demonstrate that BoNT/A acts as a zinc-dependent protease that selectively cleaves SNAP-25. Thus, a second component of the putative fusion complex mediating synaptic vesicle exocytosis is targeted by a clostridial neurotoxin.
              Article 0 comments Cited 168 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Alexander A. Mongin: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 28 February 2013
                Volume: 8
                Issue: 2
                Electronic Location Identifier: e57898
                Affiliations
                [1 ]Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
                [2 ]Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, Japan
                [3 ]UMR_S949 INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, Strasbourg, France
                Albany Medical College, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SK. Performed the experiments: YN KF YS KS YI YM. Analyzed the data: YN KF YS KS YI YM SK. Contributed reagents/materials/analysis tools: CG. Wrote the paper: YN KF YS SK.

                Article
                Publisher ID: PONE-D-12-30053
                DOI: 10.1371/journal.pone.0057898
                PMC ID: 3585279
                PubMed ID: 23469098
                SO-VID: 538c78d2-c48e-43d3-ba5e-30f655e70e91
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 3 October 2012
                Date accepted : 27 January 2013
                Page count
                Pages: 13
                Funding
                This work was supported by Study (Group) of the Health Effects of Heavy Metals Organized by Ministry of the Environment, Japan (SK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Biochemistry
                Subject: Cytochemistry
                Subject: Immunocytochemistry
                Subject: Computational Biology
                Subject: Microarrays
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Rat
                Subject: Neuroscience
                Subject: Molecular Neuroscience
                Subject: Signaling Pathways
                Subject: Neurobiology of Disease and Regeneration
                Subject: Toxicology
                Subject: Neurotoxicology
                Subject: Toxic Agents
                Subject: Mathematics
                Subject: Statistics
                Subject: Biostatistics
                Subject: Medicine
                Subject: Neurology
                Subject: Neuropharmacology

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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