Modulation of hippocampal neuron survival by thrombin and factor Xa.
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 (<or=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 IP(3) receptors of the endoplasmic reticulum. Both of the serine proteases improved the recovery of neuronal Ca2+ homeostasis after glutamate treatment.
Gorbacheva
L R
LR
Department of Human and Animal Physiology, Biological Faculty, Lomonosov Moscow State University, Moscow, 119899, Russia.
Storozhevykh
T P
TP
Pinelis
V G
VG
Ishiwata
S
S
Strukova
S M
SM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000494:pharmacology*; D005971:Glutamates / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000494:pharmacology*
D005971:Glutamates; D013917:Thrombin; D015951:Factor Xa; D002118:Calcium