Transient global
cerebral ischemia triggers suppression of the initiation step of
protein synthesis, a process which is controlled by endoplasmic reticulum (ER) function. ER function has been shown to be disturbed after
transient cerebral ischemia, as indicated by an activation of the ER-resident eIF2alpha
kinase PERK. In this study, we investigated
ischemia-induced changes in
protein levels and phosphorylation states of the
initiation factors eIF2alpha,
eIF2B epsilon, and eIF4G1 and of
p70 S6 kinase,
proteins playing a central role in the control of the initiation of translation. Transient focal
cerebral ischemia was induced in mice by occlusion of the left middle cerebral artery. Transient
ischemia caused a long-lasting suppression of global
protein synthesis. eIF2alpha was transiently phosphorylated after
ischemia, peaking at 1-3 h of recovery.
eIF2B epsilon and
p70 S6 kinase were completely dephosphorylated during
ischemia and phosphorylation did not recover completely following reperfusion. In addition,
eIF2B epsilon, eIF4G1, and
p70 S6 kinase protein levels decreased progressively with increasing recirculation time. Thus, several different processes contributed to
ischemia-induced suppression of the initiation of
protein synthesis: a long-lasting dephosphorylation of
eIF2B epsilon and p70 S6K starting during
ischemia, a transient phosphorylation of eIF2alpha during early reperfusion, and a marked decrease of
eIF2B epsilon, eIF4G1, and p70 S6K
protein levels starting during vascular occlusion (eIF4G1). Study of the mechanisms underlying
ischemia-induced suppression of the initiation step of translation will help to elucidate the role of
protein synthesis inhibition in the development of neuronal cell injury triggered by
transient cerebral ischemia.