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

Although expression of the glial glutamate transporter GLAST is tightly reg ulated during development and under pathophysiological conditions, little i s known about endogenous modulators of GLAST expression. Because growth fac tors are generally believed to regulate glial functions, we addressed their possible contribution to GLAST regulation in cultured rat astrocytes. Of t he six growth factors tested (basic fibroblast growth factor (bFGF), insuli n-like growth factor-1 (IGF-1), epidermal growth factor (EGF), insulin, pla telet-derived growth factor, and hepatocyte growth factor), bFGF, IGF-1 and EGF enhanced [H-3]glutamate transport activity in a concentration-dependen t 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 g rowth 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. Pharmacologica l 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 r esults suggest that the growth factors activate different signaling pathway s for GLAST upregulation. The present study may indicate a novel regulatory system of glial glutamate transporters.