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

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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.

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Abbreviations

APC:

activated protein C

EPCR:

endothelial protein C receptor

Hsp90:

heat shock protein 90

PAR:

proteinase-activated receptor

PAR1-AP:

PAR1 peptide agonist

PC:

protein C

PMSF:

phenylmethylsulfonyl fluoride

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Authors and Affiliations

  1. Biology Faculty, Lomonosov Moscow State University, 119899, Moscow, Russia

    L. R. Gorbacheva & S. M. Strukova

  2. Research Center of Children’s Health, Russian Academy of Medical Sciences, Moscow, Russia

    T. P. Storozhevykh, V. G. Pinelis & O. N. Davydova

  3. Department of Physics, Faculty of Science and Engineering, Waseda University, Tokyo, Japan

    S. Ishiwata

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  1. L. R. Gorbacheva
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  2. T. P. Storozhevykh
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  3. V. G. Pinelis
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  4. O. N. Davydova
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  5. S. Ishiwata
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  6. S. M. Strukova
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Correspondence to S. M. Strukova.

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Original Russian Text © L. R. Gorbacheva, T. P. Storozhevykh, V. G. Pinelis, O. N. Davydova, S. Ishiwata, S. M. Strukova, 2008, published in Biokhimiya, 2008, Vol. 73, No. 6, pp. 893–902.

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Gorbacheva, L.R., Storozhevykh, T.P., Pinelis, V.G. et al. Activated protein C via PAR1 receptor regulates survival of neurons under conditions of glutamate excitotoxicity. Biochemistry Moscow 73, 717–724 (2008). https://doi.org/10.1134/S0006297908060138

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  • DOI: https://doi.org/10.1134/S0006297908060138

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