Abstract
MK-801 and related compounds reduce excitotoxic neuronal injury by blocking N-methyl-D-aspartate (NMDA) receptor-gated ion channels. These agents also cause neuronal vacuolization and block glutamate-induced astrocyte swelling, effects that may be unrelated to actions at the NMDA receptor. In the present study, high concentrations of MK-801 (100-1,000 μM) caused uncompetitive inhibition of glutamate uptake in astrocyte and neuronal cultures and stimulated D-aspartate efflux from astrocytes. MK-801 (500 μM) reduced the maximal velocity for glutamate uptake in astrocytes from 31 to 17 nmol · mg protein-1 · min-1, whereas competitive NMDA receptor antagonists did not affect glutamate uptake. MK-801 also inhibited uptake of γ-aminobutyric acid (GABA). Because both GABA uptake and glutamate uptake are electrogenic, one mechanism by which MK-801 could inhibit uptake is by membrane depolarization. Whole cell patch-clamp recording confirmed that MK- 801 in the range of 100-1,000 μM caused dose-dependent and reversible depolarization. These concentrations are far higher than necessary to block NMDA receptors, and the findings suggest that actions at sites other than NMDA receptors could contribute to the effects of high doses of MK-801 in some experimental and clinical settings.
Original language | English (US) |
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Journal | American Journal of Physiology - Cell Physiology |
Volume | 270 |
Issue number | 5 39-5 |
State | Published - May 1996 |
Externally published | Yes |
Keywords
- γ-aminobutyric acid
- astrocyte
- glutamate uptake
- neurotoxicity
- phencyclidine
ASJC Scopus subject areas
- Clinical Biochemistry
- Cell Biology
- Physiology
- Physiology (medical)