PMID: 8967440May 1, 1996Paper

MK-801 reduces uptake and stimulates efflux of excitatory amino acids via membrane depolarization

The American Journal of Physiology
M C LonguemareR A Swanson

Abstract

MK-801 and related compounds reduce excitotoxic neuronal injury by blocking N-methyl-D-aspartate (NMDA) receptorgated 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 microM) caused uncompetitive inhibition of glutamate uptake in astrocyte and neuronal cultures and stimulated D-aspartate efflux from astrocytes. MK-801 (500 microM) 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 gamma-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 microM 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 ...Continue Reading

References

Jan 1, 1990·Journal of Neuroscience Research·P H ChanS Chen
Mar 1, 1989·Journal of Neuroscience Research·K H BackusM Schachner
Feb 15, 1995·Journal of Neuroscience Research·M C Longuemare, R A Swanson
Sep 1, 1993·Neuron·D AttwellM Szatkowski

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Citations

Oct 16, 2001·American Journal of Physiology. Cell Physiology·J LeonovaE Hansson
Oct 26, 2005·The Journal of Biological Chemistry·Alexander PanovJ Timothy Greenamyre
Nov 20, 2014·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Melissa TrotmanRobert Fern
Dec 2, 2000·Nature Neuroscience·R BetarbetJ T Greenamyre
Mar 15, 2000·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·R S DombroM D Norenberg
Sep 29, 2009·Breast Cancer Research and Treatment·William G NorthLauna Lynch
Mar 27, 2012·Biochemistry·Brian Glancy, Robert S Balaban

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