期刊
NEUROPHARMACOLOGY
卷 49, 期 6, 页码 872-882出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2005.07.014
关键词
glutamate; trafficking; EAAC1; Akt; platelet-derived growth factor; glutamate transport
资金
- NICHD NIH HHS [P30 HD26979] Funding Source: Medline
- NINDS NIH HHS [NS39011] Funding Source: Medline
Previously we have shown that plate I et-derived growth factor (PDGF) rapidly increases the activity of the neuronal glutamate transporter, EAAC1. This increase in activity is associated with a rapid (within minutes) redistribution of transporter from a subcellular compartment to the plasma membrane and is blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K). Similar effects of PI3K inhibitors have been observed for insulin-dependent up-regulation of the GLUT4 subtype of glucose transporter. Although GLUT4 regulation also depends on the serine-threonine kinase (Akt/protein kinase B), a downstream target of PI3K, the downstream effectors responsible of PDGF-dependent regulation of EAACl have not been identified. In the present study, PDGF increased the level of Akt phosphorylation (Ser 473) in C6 glioma cells, a cell line that has been used to study regulated trafficking of endogenous EAAC1 Two inhibitors of PI3K blocked this effect. In transient transfection studies, a dominant negative mutant of Akt-1 blocked PDGF-induced redistribution of epitope-tagged EAAC1 (myc-EAAC1). Conversely, constitutively active Akt-1 (CA Akt-1) increased the cell surface expression of myc-EAAC1. A lentiviral vector engineered to express CA Akt-1 increased Akt activation, cell surface expression of endogenous EAAC1, and Na(+)-dependent glutamate transport activity. Together, these studies suggest that Akt is required for PDGF-induced regulation of EAAC1. (c) 2005 Elsevier Ltd. All rights reserved.
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