Modulation of Hippocampal Neuron Survival by Thrombin and Factor Xa

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L. R. Gorbacheva¹, T. P. Storozhevykh², V. G. Pinelis², S. Ishiwata³, and S. M. Strukova^1*

¹Department of Human and Animal Physiology, Biological Faculty, Lomonosov Moscow State University, 119899 Moscow, Russia; E-mail: strukova@mail.ru

²Scientific Center for Children's Health, Russian Academy of Medical Sciences, 119991 Moscow, Russia

³Department of Physics, Faculty of Science and Engineering, Advanced Research Institute for Science and Engineering, Waseda University, Tokyo, Japan

^* To whom correspondence should be addressed.

Received April 28, 2006; Revision received June 8, 2006

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Effects of thrombin, factor Xa (FXa), and protease-activated receptor 1 and 2 agonist peptides (PAR1-AP and PAR2-AP) on survival and intracellular Ca²⁺ homeostasis in hippocampal neuron cultures treated with cytotoxic doses of glutamate were investigated. It is shown that at low concentrations (<=10 nM) thrombin and FXa protect neurons from glutamate-induced excitotoxicity. Inactivation of the proteases blocked the neuroprotective effect. Using PAR1-AP, PAR2-AP, and PAR1 antagonist, we have demonstrated that the neuroprotective effect of thrombin is mediated through activation of PAR1, whereas the effect of FXa may involve novel subtype(s) of PARs. Unlike FXa, thrombin induced transient intracellular calcium signal in hippocampal neurons, which was mainly mediated via IP₃ receptors of the endoplasmic reticulum. Both of the serine proteases improved the recovery of neuronal Ca²⁺ homeostasis after glutamate treatment.

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KEY WORDS: thrombin, factor Xa, glutamate toxicity, apoptosis, intracellular calcium, hippocampal neurons

DOI: 10.1134/S000629790610004X

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