H . Tanaka et al. Brain Research 886 2000 190 –207
195
which regulate the initiation and elongation of mature this mechanism comes from the finding of pools of
transcripts, and 2 translational repressor and enhancer AMPARs within spines [118], the high concentration of
factors. In addition, translational efficiency is influenced by NSF in the hippocampus [54,116], its high localization
transcript-specific structural motifs, which serve as recog- within hippocampal PSDs [155], and its accumulation in
nition sequences for the RNA binding proteins. These PSDs following transient cerebral ischemia [55].
include: 1 sequences residing in the 59 and 39 UTR; 2 alternate or additional 59-UTR AUG codons or their
cognate short open reading frames; 3 consensus se-
4. Regulation of GluR2 expression in
quences for RNA binding proteins; and or 4 the exact neurodegenerative disorders
nucleotide context of the initiator AUG [58]. The GluR2 transcript appears to be under negative
4.1. Ischemia translational control. The presence of the 59-UTR region in
the GluR2 transcript suppresses translation of GluR2 in 4.1.1. Global ischemia-induced suppression of GluR2
Xenopus oocytes and in cell-free reticulocyte lysates [92]. mRNA and subunit expression
The longest GluR2 transcripts identified in vivo, beginning Global ischemia during cardiac arrest affects 150,000
481 bases downstream from the AUG, exhibit greatly Americans each year and in many cases results in delayed
reduced translational efficiency by about 40- to 50-fold onset of neurological deficits [112]. In addition, open heart
relative to the GluR2 transcript containing only a seven- surgery can cause brain ischemia [14,119,140]. Transient,
base leader when assayed in reticulocyte lysates [67,92]. severe global or forebrain ischemia, observed in patients
The region with the greatest suppressor activity |20-fold during cardiorespiratory arrest, cardiac surgery or ex-
overlaps all identified transcription initiation sites and perimentally in animals, induces selective and delayed
includes two of the five upstream AUG codons and a neuronal death [14,119,140]. Pyramidal neurons in the
40-nucleotide imperfect GU repeat. Although the mecha- CA1 region of the hippocampus are particularly vulner-
nism for translational suppression by the GluR2 59-UTR able. Histological evidence of degeneration, exhibiting the
has yet to be identified, the upstream AUGs on their own hallmarks of apoptosis, is not observed until two to three
exert only minor suppression of translation [91]. days after induction of ischemia in rats [25,64,115,121].
The delayed cell death after ischemia requires an early rise
21 21
in Ca in CA1 and initial translocation of Zn
from
3. GluR2 receptor targeting and trafficking presynaptic neurons at CA1 synapses. During the ischemic
