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Volume 16, Number 17,
Issue of September 1, 1996
pp. 5393-5404
Copyright ©1996 Society for Neuroscience
Mechanisms of H+ and Na+ Changes Induced
by Glutamate, Kainate, and D-Aspartate in Rat Hippocampal
Astrocytes
Received April 17, 1996; revised June 7, 1996; accepted June 14, 1996.
Christine R. Rose1 and
Bruce R. Ransom2
1 Department of Neurology, Yale University School of
Medicine, New Haven, Connecticut 06510, and 2 Department of
Neurology, University of Washington School of Medicine, Seattle,
Washington 98195-6465
The excitatory transmitter glutamate (Glu), and its analogs
kainate (KA), and D-aspartate (D-Asp)
produce significant pH changes in glial cells. Transmitter-induced pH
changes in glial cells, generating changes in extracellular pH, may
represent a special form of neuronal-glial interaction. We
investigated the mechanisms underlying these changes in intracellular
H+ concentration ([H+]i) in
cultured rat hippocampal astrocytes and studied their correlation with
increases in intracellular Na+ concentration
([Na+]i), using fluorescence ratio imaging
with 2 ,7-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) or
sodium-binding benzofuran isophthalate (SBFI). Glu, KA, or
D-Asp evoked increases in [Na+]i;
Glu or D-Asp produced parallel acidifications. KA,
in contrast, evoked biphasic changes in
[H+]i, alkaline followed by acid shifts,
which were unaltered after Ca2+ removal and persisted in 0 Cl -saline, but were greatly reduced in
CO2/HCO3-free or Na+-free
saline, or during 4,4-diisothiocyanato-stilbene-2,2-disulphonic acid
(DIDS) application. The non-NMDA receptor antagonist
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocked KA-evoked
changes in [H+]i and
[Na+]i, indicating that they were
receptor-ionophore mediated. In contrast, CNQX increased the
[H+]i change and decreased the
[Na+]i change induced by Glu.
D-Asp, which is transported but does not act at Glu
receptors, induced [H+]i and
[Na+]i changes that were virtually unaltered
by CNQX. Our study indicates that [Na+]i
increases are not primarily responsible for Glu- or KA-induced
acidifications in astrocytes. Instead, intracellular acidifications
evoked by Glu or D-Asp are mainly caused by transmembrane
movement of acid equivalents associated with Glu/Asp-uptake into
astrocytes. KA-evoked biphasic [H+]i
changes, in contrast, are probably attributable to transmembrane ion
movements mediated by inward, followed by outward, electrogenic
Na+/HCO3 cotransport, reflecting
KA-induced biphasic membrane potential changes.
Key words:
glial cell;
glutamate;
kainate;
aspartate;
intracellular
sodium;
intracellular pH;
ion regulation;
glutamate transport;
ionotropic glutamate receptor;
Na+/HCO3
cotransport
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