Activated Protein C Is the Regulator of the NF-κB Activity under the Conditions of Glutamate Toxicity

Activated protein C (APC) is one of the key proteinases of hemostasis exhibiting anti-coagulant, anti-inflammatory, and protective functions. In the present work, the anti-apoptotic action of the proteinase in low concentrations is shown on the glutamate toxicity model in cultured hippocampal neurons. It is demonstrated that high concentrations of glutamate leads to translocation of subunit p65 of transcription factor NF-kappa B into nucleus, and low concentrations of APC prevents the effect of the neurotransmitter. Moreover, helenalin, a specific inhibitor of NF-kappa Bp65, similar to APC, increased survival of neurons in toxicity conditions. Using specific blocking antibodies we have revealed that the APC via its own receptor (endothelial protein C receptor) and protease activated receptor 1 (PAR1) inhibits glutamate-induced activation of transcription factor NF-kappa B. Thus, APC in low concentrations protects hippocampal neurons from glutamate-induced death through a receptor-dependent regulation of the activity of p65 subunit of transcription factor NF-kappa B.