MECHANISMS OF RAT GLUR2 GENE EXPRESSION IN NEURONS

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A growing body of literature shows that GluR2 mRNA levels are down- regulated in specific neurons following epileptiform-like activity and global ischemia in rats. The selective loss of GluR2 in neurons would favor enhanced calcium entry via AMPA receptors into these cells and could exacerbate or initiate local excitotoxicity, since recombinant AMPA receptors lacking a GluR2 subunit exhibit high calcium permeability. For this reason we are interested in exploring specifically how neurons regulate expression of this key subunit. this primary focus of this proposal is to identify the critical regulatory elements FluR2 promoter that control GluR2 expression in neurons. We have subcloned and sequenced the 5'-flanking region of the rat GluR2 gene and have identified multiple regions governing GluR2 expression in neurons. Based on our preliminary data, we proposed that the GluR2 promoter contains both a positive, neuron-specific enhancer region that promotes expression in neurons, as well as a neuron specific silencer region that represses GluR2 expression in non-neuronal cells. We hypothesize that changes in the expression of the transcription factors that recognize these regulatory sites may lead to changes in GluR2 levels that exacerbate or initiate excitotoxicity. The long-term goal of these experiments is to develop a new strategy for stroke therapy based on preventing the loss of the GluR2 subunit.