Role of 3' untranslated regions in translation regulation of Glur2 mRNAs

GluR2 expression is regulated at the transcription level by cell-specific transcription factors that target the promoter, and GluR2 is also subject to translational control by the GU repeats residing in the long 5' untranslated region (UTR). In this study, the translational regulation of GluR2 mRNAs by alternative 3'UTRs was explored. GluR2 mRNAs exist as two major GluR2 transcripts of 6 kb and 4 kb, differing only in the length of their 3'UTRs (∼2750 bp or "long" and ∼750 bp or "short", respectively) in rats and mice. Both short and long GluR2 mRNAs are abundantly expressed in CA1 and CA3 pyramidal neurons, and dentate granule cells (DG). Pilocarpine-induced status epilepticus (SE) significantly reduced GluR2 mRNA levels in CA1 and CA3 but not DG. In Xenopus oocytes, the expression profiles of luciferase reporters bearing alternative GluR2 5' and 3' UTRs were studied. In the absence of long 5'UTR, which contains translation repressor elements, the long 3'UTR serves as a translational suppressor for GluR2 transcripts. In rat hippocampus, the majority of endogenous GluR2 transcripts exhibited strong association with polysomes, which is indicative of active translation, whereas GluR2 transcripts bearing long 3'UTRs were associated with ribosome-free ribonucleoprotein complexes. A de-repression of translation of GluR2 mRNAs bearing long 3'UTRs after prolonged seizures was observed. The mechanism of the long 3'UTR mediated translation repression was studied using the luciferase reporter mRNAs bearing alternative GluR2 UTRs in rabbit reticulocyte lysates treated with translation elongation inhibitors and translation initiation modulators. Translation of the reporter mRNAs bearing the long GluR2 3'UTR was insensitive to low concentrations of the elongation inhibitors cycloheximide and anisomycin, in contrast to a reporter bearing the short 3'UTR, which was inhibited, suggesting that initiation is the site of translation regulation for GluR2 mRNAs bearing the long 3'UTRs. The translation initiation modulator kasugamycin selectively induced the expression of reporter mRNAs bearing either of the long UTRs of GluR2. These findings overall suggest that GluR2 transcripts have distinct translation patterns due to alternative 5' and 3'UTRs. The mechanisms of UTR-mediated translation regulation present potential targets for therapeutic modulation of GluR2 expression in a transcript-specific manner.