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Vol. 62, Issue 4, 901-910, October 2002
Departments of Pediatrics and Pharmacology, Children's Hospital of
Philadelphia (M.I.G., M.B.R.), and Department of Pharmacology, Center
for Experimental Therapeutics (M.G.K.), University of Pennsylvania,
Philadelphia, Pennsylvania
In previous studies, we have shown that activation of protein kinase C
(PKC) rapidly (within minutes) increases the activity and cell surface
expression of the glutamate transporter EAAC1 in two systems that
endogenously express this transporter (C6 glioma cells and cocultures
of neurons and astrocytes). However, the magnitude of the increase in
activity is greater than the increase in cell surface expression. In
addition, certain compounds completely block the increase in cell
surface expression but only partially attenuate the increase in
activity. We hypothesized that PKC increases EAAC1 activity by
increasing cell surface expression and catalytic efficiency and that
two different subtypes of PKC mediate these effects. To address these
hypotheses, the PKC subtypes expressed by C6 glioma cells were
identified. Of the PKC subtypes that are activated by phorbol esters,
only PKC
, PKC
, and PKC
were observed. Gö6976, a compound
that blocks PKC at concentrations that do not inhibit PKC or
PKC, partially inhibited the increase in uptake but completely
abolished the increase in EAAC1 cell surface expression. The
`Gö6976-insensitive' increase in activity was not associated
with a change in total transporter expression but was associated with
an increase in the Vmax.
Na+-dependent glycine transport was not increased,
providing indirect evidence that the Gö6976-insensitive
increase in activity was not caused by a change in the Na+
electrochemical gradient required for activity. Finally, by
down-regulating different subtypes of PKC, we found evidence that
PKC mediates the increase in EAAC1 activity that is independent of
changes in cell surface expression and found further evidence that
PKC mediates the increase in cell surface expression. The potential relationship of the present work with a previously identified role for
PKC in certain forms of synaptic plasticity is discussed.
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