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Transient upregulation of the glial glutamate transporter GLAST in response to fibroblast growth factor, insulin-like growth factor and epidermal growth factor in cultured astrocytes

¹ Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
² Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 180-8611, Japan

*Author for correspondence (e-mail: ikegaya{at}tk.airnet.ne.jp)

Accepted July 9, 2001

Although expression of the glial glutamate transporter GLAST is tightly regulated during development and under pathophysiological conditions, little is known about endogenous modulators of GLAST expression. Because growth factors are generally believed to regulate glial functions, we addressed their possible contribution to GLAST regulation in cultured rat astrocytes. Of the six growth factors tested (basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), insulin, platelet-derived growth factor, and hepatocyte growth factor), bFGF, IGF-1 and EGF enhanced [³H]glutamate transport activity in a concentration-dependent manner. These effects were accompanied by an increase in the V_max value for transport activity and in GLAST protein and mRNA levels, which suggests that GLAST expression is transcriptionally regulated by the growth factors. Interestingly, the effects reached a peak after 36 hours of exposure to growth factors, and rapidly returned to baseline by 48 hours. A combination of IGF-1 with either bFGF or EGF showed an additive effect on the glutamate uptake activity, but a combination of bFGF and EGF did not. Pharmacological blockade of protein kinase C inhibited the effects of IGF-1 and EGF, but not bFGF. By contrast, genistein, an inhibitor of tyrosine kinases, blocked the effects of bFGF and EGF without affecting the effect of IGF-1. These results suggest that the growth factors activate different signaling pathways for GLAST upregulation. The present study may indicate a novel regulatory system of glial glutamate transporters.

Key words: Astrocyte, GLT-1, Basic fibroblast growth factor, Epidermal growth factor, Insulin, Platelet-derived growth factor, Hepatocyte growth factor

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