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(Received for publication, February 21, 1996, and in revised form, August 1, 1996)
From the Department of Anatomy, Institute of Basic Medical
Sciences, University of Oslo, P. O. Box 1105 Blindern,
N-0317 Oslo, Norway, Removal of excitatory amino acids from the
extracellular fluid is essential for synaptic transmission and for
avoiding excitotoxicity. The removal is accomplished by glutamate
transporters located in the plasma membranes of both neurons and
astroglia. The uptake system consists of several different transporter
proteins that are carefully regulated, indicating more refined
functions than simple transmitter inactivation. Here we show by
chemical cross-linking, followed by electrophoresis and immunoblotting,
that three rat brain glutamate transporter proteins (GLAST, GLT and
EAAC) form homomultimers. The multimers exist not only in intact brain
membranes but also after solubilization and after reconstitution in
liposomes. Increasing the cross-linker concentration increased the
immunoreactivity of the bands corresponding to trimers at the expense
of the dimer and monomer bands. However, the immunoreactivities of the
dimer bands did not disappear, indicating a mixture of dimers and
trimers. GLT and GLAST do not complex with each other, but as
demonstrated by double labeling post-embedding electron microscopic
immunocytochemistry, they co-exist side by side in the same astrocytic
cell membranes. The oligomers are held together noncovalently in
vivo. In vitro, oxidation induces formation of
covalent bonds (presumably -S-S-) between the subunits of the
oligomers leading to the appearance of oligomer bands on
SDS-polyacrylamide gel electrophoresis. Immunoprecipitation experiments
suggest that GLT is the quantitatively dominant glutamate
transporter in the brain. Radiation inactivation analysis gives a
molecular target size of the functional complex corresponding to
oligomeric structure. We postulate that the glutamate transporters
operate as homomultimeric complexes.
Volume 271, Number 44,
Issue of November 1, 1996
pp. 27715-27722
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
Novo Nordisk A/S, Novo Nordisk
Park, DK-2760 Måløv, Denmark, and § St. Hans Mental
Hospital, Boserup vej, DK-4000 Roskilde, Denmark
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