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H(2)O(2)-mediated modulation of cytosolic signaling and organelle function in rat hippocampus.

Abstract

Reactive oxygen species (ROS) released from (dys-)functioning mitochondria contribute to normal and pathophysiological cellular signaling by modulating cytosolic redox state and redox-sensitive proteins. To identify putative redox targets involved in such signaling, we exposed hippocampal neurons to hydrogen peroxide (H(2)O(2)). Redox-sensitive dyes indicated that externally applied H(2)O(2) may oxidize intracellular targets in cell cultures and acute tissue slices. In cultured neurons, H(2)O(2) (EC(50) 118 microM) induced an intracellular Ca(2+) rise which could still be evoked upon Ca(2+) withdrawal and mitochondrial uncoupling. It was, however, antagonized by thapsigargin, dantrolene, 2-aminoethoxydiphenyl borate, and high levels of ryanodine, which identifies the endoplasmic reticulum (ER) as the intracellular Ca(2+) store involved. Intracellular accumulation of endogenously generated H(2)O(2)-provoked by inhibiting glutathione peroxidase-also released Ca(2+) from the ER, as did extracellular generation of superoxide. Phospholipase C (PLC)-mediated metabotropic signaling was depressed in the presence of H(2)O(2), but cytosolic cyclic adenosine-5'-monophosphate (cAMP) levels were not affected. H(2)O(2) (0.2-5 mM) moderately depolarized mitochondria, halted their intracellular trafficking in a Ca(2+)- and cAMP-independent manner, and directly oxidized cellular nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH(2)). In part, the mitochondrial depolarization reflects uptake of Ca(2+) previously released from the ER. We conclude that H(2)O(2) releases Ca(2+) from the ER via both ryanodine and inositol trisphosphate receptors. Mitochondrial function is not markedly impaired even by millimolar concentrations of H(2)O(2). Such modulation of Ca(2+) signaling and organelle interaction by ROS affects the efficacy of PLC-mediated metabotropic signaling and may contribute to the adjustment of neuronal function to redox conditions and metabolic supply.

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  • Authors+Show Affiliations

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    DFG Research Center Molecular Physiology of the Brain (CMPB), Zentrum für Physiologie und Pathophysiologie, Abteilung Neuro- und Sinnesphysiologie, Georg-August-Universität Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.

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    MeSH

    Adenosine Triphosphate
    Animals
    Axonal Transport
    Calcium Channel Blockers
    Calcium Signaling
    Cells, Cultured
    Cytosol
    Endoplasmic Reticulum
    Flavin-Adenine Dinucleotide
    Hippocampus
    Hydrogen Peroxide
    Inositol 1,4,5-Trisphosphate Receptors
    Kinetics
    Male
    Membrane Potential, Mitochondrial
    Mitochondria
    Movement
    NAD
    Neurons
    Organelles
    Oxidation-Reduction
    Purinergic P2 Receptor Agonists
    Rats
    Rats, Sprague-Dawley
    Reactive Oxygen Species
    Receptors, Purinergic P2

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    19430810

    Citation

    Gerich, Florian J., et al. "H(2)O(2)-mediated Modulation of Cytosolic Signaling and Organelle Function in Rat Hippocampus." Pflugers Archiv : European Journal of Physiology, vol. 458, no. 5, 2009, pp. 937-52.
    Gerich FJ, Funke F, Hildebrandt B, et al. H(2)O(2)-mediated modulation of cytosolic signaling and organelle function in rat hippocampus. Pflugers Arch. 2009;458(5):937-52.
    Gerich, F. J., Funke, F., Hildebrandt, B., Fasshauer, M., & Müller, M. (2009). H(2)O(2)-mediated modulation of cytosolic signaling and organelle function in rat hippocampus. Pflugers Archiv : European Journal of Physiology, 458(5), pp. 937-52. doi:10.1007/s00424-009-0672-0.
    Gerich FJ, et al. H(2)O(2)-mediated Modulation of Cytosolic Signaling and Organelle Function in Rat Hippocampus. Pflugers Arch. 2009;458(5):937-52. PubMed PMID: 19430810.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - H(2)O(2)-mediated modulation of cytosolic signaling and organelle function in rat hippocampus. AU - Gerich,Florian J, AU - Funke,Frank, AU - Hildebrandt,Belinda, AU - Fasshauer,Martin, AU - Müller,Michael, Y1 - 2009/05/10/ PY - 2008/10/30/received PY - 2009/04/07/accepted PY - 2009/04/06/revised PY - 2009/5/12/entrez PY - 2009/5/12/pubmed PY - 2010/2/3/medline SP - 937 EP - 52 JF - Pflugers Archiv : European journal of physiology JO - Pflugers Arch. VL - 458 IS - 5 N2 - Reactive oxygen species (ROS) released from (dys-)functioning mitochondria contribute to normal and pathophysiological cellular signaling by modulating cytosolic redox state and redox-sensitive proteins. To identify putative redox targets involved in such signaling, we exposed hippocampal neurons to hydrogen peroxide (H(2)O(2)). Redox-sensitive dyes indicated that externally applied H(2)O(2) may oxidize intracellular targets in cell cultures and acute tissue slices. In cultured neurons, H(2)O(2) (EC(50) 118 microM) induced an intracellular Ca(2+) rise which could still be evoked upon Ca(2+) withdrawal and mitochondrial uncoupling. It was, however, antagonized by thapsigargin, dantrolene, 2-aminoethoxydiphenyl borate, and high levels of ryanodine, which identifies the endoplasmic reticulum (ER) as the intracellular Ca(2+) store involved. Intracellular accumulation of endogenously generated H(2)O(2)-provoked by inhibiting glutathione peroxidase-also released Ca(2+) from the ER, as did extracellular generation of superoxide. Phospholipase C (PLC)-mediated metabotropic signaling was depressed in the presence of H(2)O(2), but cytosolic cyclic adenosine-5'-monophosphate (cAMP) levels were not affected. H(2)O(2) (0.2-5 mM) moderately depolarized mitochondria, halted their intracellular trafficking in a Ca(2+)- and cAMP-independent manner, and directly oxidized cellular nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH(2)). In part, the mitochondrial depolarization reflects uptake of Ca(2+) previously released from the ER. We conclude that H(2)O(2) releases Ca(2+) from the ER via both ryanodine and inositol trisphosphate receptors. Mitochondrial function is not markedly impaired even by millimolar concentrations of H(2)O(2). Such modulation of Ca(2+) signaling and organelle interaction by ROS affects the efficacy of PLC-mediated metabotropic signaling and may contribute to the adjustment of neuronal function to redox conditions and metabolic supply. SN - 1432-2013 UR - https://www.unboundmedicine.com/medline/citation/19430810/H_2_O_2__mediated_modulation_of_cytosolic_signaling_and_organelle_function_in_rat_hippocampus_ L2 - https://dx.doi.org/10.1007/s00424-009-0672-0 DB - PRIME DP - Unbound Medicine ER -