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J Biol Chem, Vol. 275, Issue 7, 5228-5237, February 18, 2000
From the § Department of Pediatrics, Children's
Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 and the
Departments of Na+-dependent
glutamate transporters are the primary mechanism for removal of
excitatory amino acids (EAAs) from the extracellular space of the
central nervous system and influence both physiologic and pathologic
effects of these compounds. Recent evidence suggests that the activity
and cell surface expression of a neuronal subtype of glutamate
transporter, EAAC1, are rapidly increased by direct activation of
protein kinase C and are decreased by wortmannin, an inhibitor of
phosphatidylinositol 3-kinase (PI3-K). We hypothesized that this
regulation could be analogous to insulin-induced stimulation of the
GLUT4 subtype of glucose transporter, which is dependent upon
activation of PI3-K. Using C6 glioma, a cell line that endogenously and
selectively expresses EAAC1, we report that platelet-derived growth
factor (PDGF) increased Na+-dependent
L-[3H]-glutamate transport activity within 30 min. This effect of PDGF was not due to a change in total cellular
EAAC1 immunoreactivity but was instead correlated with an increase cell
surface expression of EAAC1, as measured using a membrane impermeant
biotinylation reagent combined with Western blotting. A decrease in
nonbiotinylated intracellular EAAC1 was also observed. These studies
suggest that PDGF causes a redistribution of EAAC1 from an
intracellular compartment to the cell surface. These effects of PDGF
were accompanied by a 35-fold increase in PI3-K activity and were
blocked by the PI3-K inhibitors, wortmannin and LY 294002, but not by
an inhibitor of protein kinase C. Other growth factors, including
insulin, nerve growth factor, and epidermal growth factor had no effect on glutamate transport nor did they increase PI3-K activity. These studies suggest that, as is observed for insulin-mediated translocation of GLUT4, EAAC1 cell surface expression can be rapidly increased by
PDGF through activation of PI3-K. It is possible that this PDGF-mediated increase in EAAC1 activity may contribute to the previously demonstrated neuroprotective effects of PDGF.
Platelet-derived Growth Factor Rapidly Increases Activity and
Cell Surface Expression of the EAAC1 Subtype of Glutamate Transporter
through Activation of Phosphatidylinositol 3-Kinase*
,
Neuroscience and ¶ Pharmacology,
University of Pennsylvania, Philadelphia, Pennsylvania 19104
*
This work was supported by National Institutes of Health
Grants NS29868 and NS39011 (to M. B. R.) and National
Institutes of Health predoctoral fellowship MH11977 (to K. D. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Neuroscience
Research, Abramson Pediatric Research Center, Rm. 502, 3516 Civic Center Blvd., Philadelphia, PA 19104-4318. Tel.: (215) 590-2205; Fax:
(215) 590-3779; E-mail: robinson@pharm.med.upenn.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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