GluR2 translation is inhibited by a polymorphic repeat sequence in the 5'-untranslated region (5'-UTR) of the transcript.
Expression of the AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptor subunit GluR2 is controlled not only at the level of transcription, but also by variations in the efficiency of translation, a new study suggests. Reporting in the Journal of Neuroscience, Myers et al. show that GluR2 translation is inhibited by a polymorphic repeat sequence in the 5'-untranslated region (5'-UTR) of the transcript. This finding raises the interesting possibility that neurons can regulate GluR2 protein levels through changes in transcription initiation that determine whether or not the repeat sequence is present.
AMPA receptors are composed of combinations of four types of GluR subunit: GluR1–GluR4. Because the number of GluR2 subunits in the AMPA receptor complex affects the Ca2+ permeability, rectification and single-channel conductance of AMPA receptors, variations in GluR2 expression can influence neuronal excitability. The relative expression of GluR2 is known to change in specific neuronal populations during development, after brain seizures or ischaemia, and in association with long-term potentiation.
The GluR2 gene has several transcription initiation sites, resulting in a population of GluR2 transcripts in vivo that differ in the length of their 5' leaders. Myers et al. looked at the effect on translation of specific sequence elements in the 5'-UTR by designing a series of GluR2 cDNA constructs that modelled the normal in vivo transcripts. They tested the translation abilities of these constructs in cell-free reticulocyte lysates, Xenopus oocytes and transfected neurons.
mRNA with long 5'-UTRs translated poorly compared with shorter transcripts. But it was not the initiation codons or leader length per se that affected translation. Instead, Myers et al. found that translation efficiency depended on the presence or absence of a short GU-repeat sequence in the 5'-UTR. This repeat cluster was shown to be polymorphic in humans. GluR2 transcripts that lacked the translation suppression sequence were preferentially associated with polyribosomes. Importantly, the authors showed that the relative abundance of long and short transcripts in the rat brain differed from region to region, suggesting that the choice of transcription start site is neuron specific and might contribute to variations in synaptic phenotype.
This study clearly demonstrates that GluR2 transcripts vary in their potential for translation into protein. In future, it will be important to establish whether contraction or expansion of the repeat sequence can lead to variations in GluR2 expression in different individuals. No doubt the findings of Myers et al. will inspire further studies of the regulation of GluR2 expression — and accompanying changes in neuronal excitability — in health and disease.
Rebecca Craven
References
Myers, S. J. et al. Inhibition of glutamate receptor 2 translation by a polymorphic repeat sequence in the 5'-untranslated leaders. J. Neurosci.24, 3489–3499 (2004) | Article | PubMed |
Myers, S. J. et al. Transcriptional regulation of the GluR2 gene: neural-specific expression, multiple promoters, and regulatory elements. J. Neurosci.18, 6723–6739 (1998) | PubMed |
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptor subunit 
