Activated protein C via PAR1 receptor regulates survival of neurons under conditions of glutamate excitotoxicity

L. R. Gorbacheva, T. P. Storozhevykh, V. G. Pinelis, O. N. Davydova, S. Ishiwata, S. M. Strukova

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    Abstract

    The effect of an anticoagulant and cytoprotector blood serine proteinase-activated protein C (APC)-on survival of cultured hippocampal and cortical neurons under conditions of glutamate-induced excitotoxicity has been studied. Low concentrations of APC (0.01-10 nM) did not cause neuron death, but in the narrow range of low concentrations APC twofold and stronger decreased cell death caused by glutamate toxicity. High concentrations of APC (> 50 nM) induced the death of hippocampal neurons similarly to the toxic action of glutamate. The neuroprotective effect of APC on the neurons was mediated by type 1 proteinase-activated receptor (PAR1), because the inactivation of the enzyme with phenylmethylsulfonyl fluoride or PAR1 blockade by a PAR1 peptide antagonist ((Tyr1)-TRAP-7) prevented the protective effect of APC. Moreover, APC inhibited the proapoptotic effect of 10 nM thrombin on the neurons. Geldanamycin, a specific inhibitor of heat shock protein Hsp90, completely abolished the antiapoptotic effect of 0.1 nM APC on glutamate-induced cytotoxicity in the hippocampal neurons. Thus, APC at low concentrations, activating PAR1, prevents the death of hippocampal and cortical neurons under conditions of glutamate excitotoxicity.

    Original languageEnglish
    Pages (from-to)717-724
    Number of pages8
    JournalBiochemistry (Moscow)
    Volume73
    Issue number6
    DOIs
    Publication statusPublished - 2008 Jun

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    Keywords

    • Activated protein C
    • Apoptosis
    • Geldanamycin
    • Glutamate toxicity
    • Hippocampal and cortical neurons
    • Proteinase-activated receptor

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Biochemistry

    Cite this

    Gorbacheva, L. R., Storozhevykh, T. P., Pinelis, V. G., Davydova, O. N., Ishiwata, S., & Strukova, S. M. (2008). Activated protein C via PAR1 receptor regulates survival of neurons under conditions of glutamate excitotoxicity. Biochemistry (Moscow), 73(6), 717-724. https://doi.org/10.1134/S0006297908060138