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J. Biol. Chem., Vol. 282, Issue 3, 1727-1737, January 19, 2007

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Translational Control of Glial Glutamate Transporter EAAT2 Expression^*

Guilian Tian, Liching Lai, Hong Guo, Yuan Lin, Matthew E. R. Butchbach, Yueming Chang, and Chien-liang Glenn Lin¹

From the Department of Neuroscience and Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio 43210

Glutamate is the major excitatory neurotransmitter in the central nervous system. Its activity is carefully modulated in the synaptic cleft by glutamate transporters. The glial glutamate transporter EAAT2 is the main mediator of glutamate clearance. Reduced EAAT2 function could lead to accumulation of extracellular glutamate, resulting in a form of cell death known as excitotoxicity. In amyotrophic lateral sclerosis and Alzheimer disease, EAAT2 protein levels are significantly decreased in affected areas. EAAT2 mRNA levels, however, remain constant, indicating that alterations in EAAT2 expression are due to disturbances at the post-transcriptional level. In the present study, we found that some EAAT2 transcripts contained 5'-untranslated regions (5'-UTRs) greater than 300 nucleotides. The mRNAs that bear long 5'-UTRs are often regulated at the translational level. We tested this possibility initially in a primary astrocyte line that constantly expressed an EAAT2 transcript containing the 565-nt 5'-UTR and found that translation of this transcript was regulated by many extracellular factors, including corticosterone and retinol. Moreover, many disease-associated insults affected the efficiency of translation of this transcript. Importantly, this translational regulation of EAAT2 occurred in vivo (i.e. both in primary cortical neurons-astrocytes mixed cultures and in mice). These results indicate that expression of EAAT2 protein is highly regulated at the translational level and also suggest that translational regulation may play an important role in the differential EAAT2 protein expression under normal and disease conditions.

Received for publication, October 18, 2006 , and in revised form, November 21, 2006.

^* This work was supported by National Institutes of Health Grant MH59805, the ALS Association, and the Alzheimer's Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Neuroscience, Ohio State University, 4198 Graves Hall, 333 W. 10th Ave., Columbus, OH 43210. Tel.: 614-688-5433; Fax: 614-688-8742; E-mail: lin.492{at}osu.edu.

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