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Manganese suppresses ATP-dependent intercellular calcium waves in astrocyte networks through alteration of mitochondrial and endoplasmic reticulum calcium dynamics.

Abstract

The neurotoxicity of manganese [Mn] is due in part to glutamate excitotoxicity. Release of ATP by astrocytes is a critical modulator of glutamatergic neurotransmission, which is regulated by calcium (Ca(2+)) waves that propagate through astrocytic networks in response to synaptic activity. It was postulated that Mn alters ATP-dependent intracellular Ca(2+) dynamics in astrocytes, thereby suppressing Ca(2+) wave activity. Confluent primary cultures of cortical astrocytes were loaded with the Ca(2+)-sensitive dye fluo-4 and examined by fluorescence microscopy for Ca(2+) wave activity following micropipet mechanical stimulation of a single cell. Mitochondrial Ca(2+) was evaluated by fluorescence microscopy following addition of ATP using the mitochondrial-specific Ca(2+) dye rhod-2-AM. Imaging studies revealed that pretreatment of astrocytes with 1-10 microM Mn significantly reduced the rate, area, and amplitude of mechanically induced Ca(2+) waves. This attenuation was not a result of inhibited mitochondrial calcium uptake because robust calcium waves were still observed following pretreatment of astrocytes with Ru360, an inhibitor of mitochondrial Ca(2+) uptake, either in coupling or uncoupling conditions. However, determination of endoplasmic reticulum (ER) Ca(2+) levels in cells using the sarco/endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin indicated that Mn reduced the available pool of releasable ER Ca(2+) at concentrations as low as 1 muM. Examination of ATP-stimulated changes in mitochondrial Ca(2+) indicated that, in cells pretreated with Mn, mitochondria retained high levels of Ca(2+). It is concluded that exposure of astrocytes to low concentrations of Mn(2+) results in sequestration of Ca(2+) within the mitochondria that reduces the available pool of releasable Ca(2+) within the ER, thereby inhibiting calcium wave activity.

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  • Authors+Show Affiliations

    ,

    Molecular, Cellular, and Integrative Neuroscience, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1680, USA. Ron.Tjalkens@colostate.edu

    , ,

    Source

    Brain research 1113:1 2006 Oct 03 pg 210-9

    MeSH

    Adenosine Triphosphate
    Analysis of Variance
    Animals
    Animals, Newborn
    Astrocytes
    Calcium
    Calcium Signaling
    Cells, Cultured
    Cerebral Cortex
    Dose-Response Relationship, Drug
    Endoplasmic Reticulum
    Glial Fibrillary Acidic Protein
    Immunohistochemistry
    Indoles
    Intracellular Fluid
    Manganese
    Mice
    Mice, Inbred C57BL
    Mitochondria
    Pyridoxal Phosphate
    Ruthenium Compounds
    Time Factors

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    16934782

    Citation

    Tjalkens, Ronald B., et al. "Manganese Suppresses ATP-dependent Intercellular Calcium Waves in Astrocyte Networks Through Alteration of Mitochondrial and Endoplasmic Reticulum Calcium Dynamics." Brain Research, vol. 1113, no. 1, 2006, pp. 210-9.
    Tjalkens RB, Zoran MJ, Mohl B, et al. Manganese suppresses ATP-dependent intercellular calcium waves in astrocyte networks through alteration of mitochondrial and endoplasmic reticulum calcium dynamics. Brain Res. 2006;1113(1):210-9.
    Tjalkens, R. B., Zoran, M. J., Mohl, B., & Barhoumi, R. (2006). Manganese suppresses ATP-dependent intercellular calcium waves in astrocyte networks through alteration of mitochondrial and endoplasmic reticulum calcium dynamics. Brain Research, 1113(1), pp. 210-9.
    Tjalkens RB, et al. Manganese Suppresses ATP-dependent Intercellular Calcium Waves in Astrocyte Networks Through Alteration of Mitochondrial and Endoplasmic Reticulum Calcium Dynamics. Brain Res. 2006 Oct 3;1113(1):210-9. PubMed PMID: 16934782.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Manganese suppresses ATP-dependent intercellular calcium waves in astrocyte networks through alteration of mitochondrial and endoplasmic reticulum calcium dynamics. AU - Tjalkens,Ronald B, AU - Zoran,Mark J, AU - Mohl,Brianne, AU - Barhoumi,Roula, Y1 - 2006/08/28/ PY - 2006/05/02/received PY - 2006/07/11/revised PY - 2006/07/12/accepted PY - 2006/8/29/pubmed PY - 2006/12/14/medline PY - 2006/8/29/entrez SP - 210 EP - 9 JF - Brain research JO - Brain Res. VL - 1113 IS - 1 N2 - The neurotoxicity of manganese [Mn] is due in part to glutamate excitotoxicity. Release of ATP by astrocytes is a critical modulator of glutamatergic neurotransmission, which is regulated by calcium (Ca(2+)) waves that propagate through astrocytic networks in response to synaptic activity. It was postulated that Mn alters ATP-dependent intracellular Ca(2+) dynamics in astrocytes, thereby suppressing Ca(2+) wave activity. Confluent primary cultures of cortical astrocytes were loaded with the Ca(2+)-sensitive dye fluo-4 and examined by fluorescence microscopy for Ca(2+) wave activity following micropipet mechanical stimulation of a single cell. Mitochondrial Ca(2+) was evaluated by fluorescence microscopy following addition of ATP using the mitochondrial-specific Ca(2+) dye rhod-2-AM. Imaging studies revealed that pretreatment of astrocytes with 1-10 microM Mn significantly reduced the rate, area, and amplitude of mechanically induced Ca(2+) waves. This attenuation was not a result of inhibited mitochondrial calcium uptake because robust calcium waves were still observed following pretreatment of astrocytes with Ru360, an inhibitor of mitochondrial Ca(2+) uptake, either in coupling or uncoupling conditions. However, determination of endoplasmic reticulum (ER) Ca(2+) levels in cells using the sarco/endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin indicated that Mn reduced the available pool of releasable ER Ca(2+) at concentrations as low as 1 muM. Examination of ATP-stimulated changes in mitochondrial Ca(2+) indicated that, in cells pretreated with Mn, mitochondria retained high levels of Ca(2+). It is concluded that exposure of astrocytes to low concentrations of Mn(2+) results in sequestration of Ca(2+) within the mitochondria that reduces the available pool of releasable Ca(2+) within the ER, thereby inhibiting calcium wave activity. SN - 0006-8993 UR - https://www.unboundmedicine.com/medline/citation/16934782/Manganese_suppresses_ATP_dependent_intercellular_calcium_waves_in_astrocyte_networks_through_alteration_of_mitochondrial_and_endoplasmic_reticulum_calcium_dynamics_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(06)02136-6 DB - PRIME DP - Unbound Medicine ER -