Protein synthesis inhibition occurs in neurons immediately on reperfusion after
ischemia and involves at least alterations in
eukaryotic initiation factors 2 (
eIF2) and 4 (eIF4). Phosphorylation of the alpha subunit of
eIF2 [
eIF2(alphaP)] by the endoplasmic reticulum transmembrane eIF2alpha
kinase PERK occurs immediately on reperfusion and inhibits translation initiation. PERK activation, along with depletion of endoplasmic reticulum Ca2+ and inhibition of the endoplasmic reticulum
Ca2+ -ATPase, SERCA2b, indicate that an endoplasmic reticulum unfolded protein response occurs as a consequence of
brain ischemia and reperfusion. In mammals, the upstream unfolded protein response components PERK, IRE1, and ATF6 activate prosurvivial mechanisms (e.g., transcription of
GRP78, PDI, SERCA2b ) and proapoptotic mechanisms (i.e., activation of Jun N-terminal
kinases,
caspase-12, and CHOP transcription). Sustained
eIF2(alphaP) is proapoptotic by inducing the synthesis of ATF4, the
CHOP transcription factor, through "bypass scanning" of 5' upstream open-reading frames in ATF4
messenger RNA; these upstream open-reading frames normally inhibit access to the ATF4 coding sequence.
Brain ischemia and reperfusion also induce
mu-calpain-mediated or caspase-3-mediated proteolysis of
eIF4G, which shifts message selection to
m 7 G-cap-independent translation initiation of messenger RNAs containing
internal ribosome entry sites. This
internal ribosome entry site-mediated translation initiation (i.e., for apoptosis-activating factor-1 and death-associated
protein-5) can also promote apoptosis. Thus, alterations in
eIF2 and eIF4 have major implications for which messenger RNAs are translated by residual
protein synthesis in neurons during brain reperfusion, in turn constraining
protein expression of changes in gene transcription induced by
ischemia and reperfusion. Therefore, our current understanding shifts the focus from
protein synthesis inhibition to the molecular pathways that underlie this inhibition, and the role that these pathways play in prosurvival and proapoptotic processes that may be differentially expressed in vulnerable and resistant regions of the reperfused brain.