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Regulation of initiation factors controlling protein synthesis on cultured astrocytes in lactic acid-induced stress

Authors

  • Nadine Vantelon,

    1. Research Group on Brain Aging, University of Poitiers, Pôle de Biologie Santé, EA 3808, 40 avenue du Recteur Pineau, F-86022 Poitiers, France
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  • Agnès Rioux-Bilan,

    1. Research Group on Brain Aging, University of Poitiers, Pôle de Biologie Santé, EA 3808, 40 avenue du Recteur Pineau, F-86022 Poitiers, France
    2. Department of Clinical Pharmacology, University Hospital, Poitiers, France
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  • Sabrina Ingrand,

    1. Research Group on Brain Aging, University of Poitiers, Pôle de Biologie Santé, EA 3808, 40 avenue du Recteur Pineau, F-86022 Poitiers, France
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  • Stéphanie Pain,

    1. Research Group on Brain Aging, University of Poitiers, Pôle de Biologie Santé, EA 3808, 40 avenue du Recteur Pineau, F-86022 Poitiers, France
    2. Department of Clinical Pharmacology, University Hospital, Poitiers, France
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  • Guylène Page,

    1. Research Group on Brain Aging, University of Poitiers, Pôle de Biologie Santé, EA 3808, 40 avenue du Recteur Pineau, F-86022 Poitiers, France
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  • Olivier Guillard,

    1. Research Group on Brain Aging, University of Poitiers, Pôle de Biologie Santé, EA 3808, 40 avenue du Recteur Pineau, F-86022 Poitiers, France
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  • Laurence Barrier,

    1. Research Group on Brain Aging, University of Poitiers, Pôle de Biologie Santé, EA 3808, 40 avenue du Recteur Pineau, F-86022 Poitiers, France
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  • Alain Piriou,

    1. Research Group on Brain Aging, University of Poitiers, Pôle de Biologie Santé, EA 3808, 40 avenue du Recteur Pineau, F-86022 Poitiers, France
    2. Department of Clinical Pharmacology, University Hospital, Poitiers, France
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  • Bernard Fauconneau

    1. Research Group on Brain Aging, University of Poitiers, Pôle de Biologie Santé, EA 3808, 40 avenue du Recteur Pineau, F-86022 Poitiers, France
    2. Department of Clinical Pharmacology, University Hospital, Poitiers, France
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Professor Bernard Fauconneau, as above.
E-mail: bernard.fauconneau@univ-poitiers.fr

Abstract

The goals of this work were first to assess whether the lactic acidosis observed in vivo in ischemia may by itself explain the inhibition of protein synthesis described in the literature and second to study the factors controlling the initiation of protein synthesis under lactic acid stress. Primary rat astrocyte cultures exposed to pH 5.25 underwent cell death and a strong inhibition of protein synthesis assessed by [3H]methionine incorporation, which was solely due to acidity of the extracellular medium and was not related to lactate concentrations. This result was associated with a weak phosphorylation of eukaryotic initiation factor (eIF)4E and a rapid phosphorylation of eIF2α via the kinases PKR and PKR-like endoplasmic reticulum kinase. The inhibition of PKR by PRI led first to a significant but not complete dephosphorylation of eIF2α that probably contributed to maintain the inhibition of the protein synthesis and second to surprising phosphorylations of extracellular signal-regulated protein kinase, p70S6K and eIF4E, suggesting a possible cross-link between the two pathways. Conversely, cell death was weak at pH 5.5. Protein synthesis was decreased to a lesser extent, the phosphorylation of eIF2α was limited, extracellular signal-regulated protein kinase 1/2 was activated and its downstream targets, p70S6K and eIF4E, were phosphorylated. However, the strong phosphorylation of eIF4E was not associated with an activation of the eIF4F complex. This last result may explain why protein synthesis was not stimulated at pH 5.5. However, when astrocytes were exposed at pH 6.2, corresponding to the lower pH observed in hyperglycemic ischemia, no modification in protein synthesis was observed. Consequently, lactic acidosis cannot, by itself, provide an explanation for the decrease in protein synthesis previously reported in vivo in ischemia.

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